Archive for the ‘Genomic Medicine’ Category

Gene Linked to Asperger Syndrome, Empathy

In Autism Spectrum Disorders, Genes, Genomic Medicine, Neuropsychology on Friday, 20 December 2013 at 16:52


Gene Linked to Asperger Syndrome, Empathy

Scientists have confirmed that variations in a particular gene play a key role in the autism spectrum condition known as Asperger Syndrome. They have also found that variations in the same gene are also linked to differences in empathy levels in the general population. 

A study published this month in the journal Molecular Autismconfirms previous research that people with Asperger Syndrome (AS) are more likely to carry specific variations in a particular gene. More strikingly, the study supports existing findings that the same gene is also linked to how much empathy typically shown by individuals in the general population.

The research was carried out by a team of researchers led by Professor Simon Baron-Cohen at the Autism Research Centre at Cambridge University. Asperger Syndrome is an autism spectrum condition. The researchers looked for sequence variations (called single nucleotide polymorphisms or SNPs) in the gene known as GABRB3 in a total of 530 adults- 118 people diagnosed with AS and 412 people without a diagnosis.

The team found that certain SNPs in GABRB3 were significantly more common in people with AS. They also discovered that additional genetic variations in the same gene were linked to scores on an empathy measure called the Empathy Quotient (EQ) in the general population.

AS is diagnosed when a person struggles with social relationships and communication, and shows unusually narrow interests and resistance to change, but has good intelligence and language skills. Most genetic studies of autistic spectrum conditions treat autism as if they are all very similar, whereas in reality there is considerable variation (e.g., in language level and intellectual ability).

Rather than studying people on the autistic condition spectrum, this new study looked only people with AS, as a well-defined subgroup of individuals within this range. The researchers examined the gene GABRB3 which regulates the functioning of a neurotransmitter called gamma-aminobutyric acid (GABA) and which contains a number of SNPs that vary across the population.

The volunteers were tested for 45 SNPs within this key gene. The team had previously found that SNPs in this gene were more common in adults with AS and also showed a relationship with empathy levels and tactile sensitivity (how sensitive people are to being touched) in the general population.


Testing a new sample of volunteers who had not taken part in previous studies, the researchers found that three of the SNPs were again more common in adults with AS, and two different SNPs in the same gene were again related to empathy levels in the general population, confirming that the gene is involved in autism spectrum conditions.

Baron-Cohen said: “We are excited that this study confirms that variation in GABRB3 is linked not just to AS but to individual differences in empathy in the population. Many candidate genes do not replicate across studies and across different samples, but this genetic finding seems to be a solid result. Research now needs to focus on where this gene is expressed in the brain in autism, and how it interacts with other genetic and non-genetic factors that cause AS.”

The team was co-led by Dr. Bhismadev Chakrabarti from the Department of Psychology at Reading University. “Genes play an important role in autism and Asperger Syndrome. This new study adds to evidence that GABRB3 is a key gene underlying these conditions. This gene is involved in the functioning of a neurotransmitter that regulates excitation and inhibition of nerve cell activity so the research gives us vital additional information about how the brain may develop differently in people with Asperger Syndrome,” he said.

Varun Warrier, who carried out the study as part of his graduate research at Cambridge University, added: “The most important aspect of this research is that it points to common genetic variants in GABRB3 being involved in both AS and in empathy as a dimensional trait. Although GABRB3 is not the only gene to be involved in this condition and in empathy levels, we are confident that we have identified one of the key players. We are following this up by testing how much protein GABRB3 produces in the brain in autism, since a genetic finding of this kind becomes more explanatory when we can also measure its function.”

Source: Cambridge University

Retrieved from: http://www.biosciencetechnology.com/news/2013/12/gene-linked-asperger-syndrome-empathy?goback=%2Egde_2514160_member_5819480722708119555#%21


gender may have more to do with autism than we thought…

In Autism Spectrum Disorders, Genes, Genomic Medicine on Thursday, 21 February 2013 at 15:33

Female Sex May Protect Against Autism

By: Megan Brooks

Autistic behaviors may be less common in girls because girls are less susceptible to some of the genetic and environmental factors that increase risk for autistic spectrum disorders (ASDs), new research suggests.

“There is a well-established sex bias in ASDs — specifically, the overall male to female ratio is about 4:1,” Elise Robinson, ScD, of the Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News.

“We were interested in better understanding that pattern through the lens of a potential female protective effect. In other words — are females affected less frequently because they are less susceptible to some of the genetic and environmental factors that create risk for ASDs? That is the primary implication of the study, and it will need to be replicated in future efforts,” Dr. Robinson said.

The study was published online February 19 in Proceedings of the National Academy of Sciences.

Investigators examined data from 2 large, independent cohorts of fraternal twins: 3842 12-year-old twin pairs in the UK-based Twin’s Early Development Study, and 6040 9- to 12-year-old twin pairs in the Swedish Child and Adolescent Twin Study.

In both groups, they compared sibling autistic traits between female and male probands, who were identified as scoring in the top 90th and 95th percentiles of the population autistic trait distributions.

In both study groups, siblings of female probands displayed significantly greater average impairments than the siblings of male probands. This suggests that girls may require greater “etiologic load” to manifest autistic behavior, the authors note.

Reached for comment, Richard E. D’Alli, MD, chief of the Division of Child Development and Behavioral Health from Duke Medicine in Durham, North Carolina, who was not involved in the study, cautioned that there really “isn’t anything new here,” and he does not think it “moves the science forward.”

“If you really believed that the female organism was different in some way to the male organism, that would explain why 5 times as many boys are afflicted with autism. Then you’d be looking for something that has something to do with the development of the disease,” he told Medscape Medical News.

“For example, if there are certain circuits in the brain that we know or certain biochemical events that occur during development that predisposes a kid to autism, you’d ask, ‘Is there a kind of difference in either the neurohormonal makeup of the female brain compared with the male brain that makes the male brain more sensitive to development of these aberrant circuits?’ You would be looking for a neurochemical, or a neurohormonal, or a neuroelectrical circuity difference,” Dr. D’Alli said.

Dr. Robinson said her team pursued the study “primarily for its research implications.”

“A female protective effect, which we found evidence for, would suggest that a greater average concentration of risk factors may be associated with ASDs in girls as compared to ASDs in boys. If our findings are replicated, this knowledge could help us pursue genetic and environmental studies of ASDs more efficiently, and better interpret our findings,” she said.

The authors and Dr. D’Alli have disclosed no relevant financial relationships.

Proc Natl Acad Sci. Published online February 19, 2013. Abstract

Retrieved from: http://www.medscape.com/viewarticle/779650?src=nl_topic

Examining and interpreting the female protective effect against autistic behavior

Elise B. Robinson, Paul Lichtenstein, Henrik Anckarsäter, Francesca Happé, and Angelica Ronald


Male preponderance in autistic behavioral impairment has been explained in terms of a hypothetical protective effect of female sex, yet little research has tested this hypothesis empirically. If females are protected, they should require greater etiologic load to manifest the same degree of impairment as males. The objective of this analysis was to examine whether greater familial etiologic load was associated with quantitative autistic impairments in females compared with males. Subjects included 3,842 dizygotic twin pairs from the Twins Early Development Study (TEDS) and 6,040 dizygotic twin pairs from the Child and Adolescent Twin Study of Sweden (CATSS). In both samples, we compared sibling autistic traits between female and male probands, who were identified as children scoring in the top 90th and 95th percentiles of the population autistic trait distributions. In both TEDS and CATSS, siblings of female probands above the 90th percentile had significantly more autistic impairments than the siblings of male probands above the 90th percentile. The siblings of female probands above the 90th percentile also had greater categorical recurrence risk in both TEDS and CATSS. Results were similar in probands above the 95th percentile. This finding, replicated across two nationally-representative samples, suggests that female sex protects girls from autistic impairments and that girls may require greater familial etiologic load to manifest the phenotype. It provides empirical support for the hypothesis of a female protective effect against autistic behavior and can be used to inform and interpret future gene finding efforts in autism spectrum disorders.

Retrieved from: http://www.pnas.org/content/early/2013/02/13/1211070110.abstract?cited-by=yes&legid=pnas;1211070110v1#cited-by



what causes depression? a possible answer.

In Genes, Genomic Medicine, Mood Disorders, Neuropsychology, Neuroscience, Psychiatry, Psychopharmacology on Thursday, 21 February 2013 at 06:54

Potential Cause of Depression Identified

By: Meagan Brooks

A protein involved in synaptic structure has been identified as a potential cause of depression, a finding that according to researchers has “enormous therapeutic potential for the development of biomarkers and novel therapeutic agents.”

Investigators at the Mount Sinai School of Medicine in New York City found decreased expression of Rac1 in the postmortem brains of people with major depressive disorder (MDD) and in mice subjected to chronic stress. They were able to control the depressive response in mice by manipulating the expression of Rac1.

“Our study is among only a few in depression research in which 2 independent human cohorts and animal models validate each other. Rac1 has enormous therapeutic potential, and I look forward to investigating it further,” study investigator Scott

Looking for Drug Targets

Rac1 is a small Rho GTPase protein involved in modulating synaptic structure.

“There is a hypothesis that depression and stress disorders are caused by a restructuring of brain circuitry,” Dr. Russo explained in an interview with Medscape Medical News.

The scientists subjected mice to repeated bouts of social stress and then evaluated the animals for changes in gene expression in the nucleus accumbens (NAc), the brain’s reward center.

The researchers found that expression of Rac1 was significantly downregulated in the brains of mice for at least 35 days following the end of the chronic social stressor. Rac1 was not affected by only a single episode of stress, indicating that only prolonged stressors that induce depression are capable of downregulating Rac1.

The scientists note that chronic stress in the mice caused epigenetic changes in chromatin that led to Rac1 downregulation.

They were able to control the depressive response to chronic stress to some extent by chronic antidepressant treatment. Histone deacetylase (HDAC) inhibitors were “extremely effective in both normalizing the reduction in Rac1 and also promoting antidepressant responses,” Dr. Russo told Medscape Medical News.

“What we think is happening is that chronic stress leads to a lasting change in the ability of our genes to transcribe this RAC1 gene, and if you target the epigenome, you can reverse that loss of Rac1 and promote synapses and more normal healthy responses,” he said.

As in the mice, Rac1 expression was also strongly downregulated in the NAc in postmortem brains of patients with MDD, who displayed similar epigenetic changes. In most of the individuals with MDD who were taking antidepressants at the time of death, Rac1 expression was not restored to the levels seen in control participants, “suggesting a need for more direct RAC1-targeting strategies to achieve therapeutic effects,” the authors write.

“Currently, there aren’t any approved drugs or even experimental drugs that target Rac1 that are safe and effective,” Dr. Russo said. “It would be nice if we could team up with some chemists or pharma and figure out if there are some safe and effective Rac activators.”

However, there are caveats to that, he said.

“It might be difficult to target Rac specifically, because it is involved in cell proliferation and restructuring so it may be difficult to get a compound that doesn’t cause cancer. It might be better to screen for targets that more generally regulate synaptic plasticity. Ketamine is a drug that does this, and there is huge interest in ketamine” in depression, Dr. Russo said.

Experts Weigh In

Commenting on the findings for Medscape Medical News, David Dietz, PhD, assistant professor of pharmacology and toxicology, State University of New York at Buffalo, who was not involved in the research, said the study “is exquisitely well done. The researchers did an excellent job of translating their findings in the rodent model to the human condition.”

Maria V. Tejada-Simon, PhD, who also was not involved in this research but who has studied Rac1, noted that her group has been “highlighting the importance of Rac1 in the brain in general, and in psychiatric diseases in particular, for a while now. Therefore, I am not surprised that Rac1 has been found to be also associated to stress disorders and depression.”

“Mood disorders have been linked to changes in synaptic structure, and it is certain that small GTPases such as Rac1 have a tremendous role as modulators of these processes. However, we need to understand that alterations in Rac1 signaling are not likely to be the primary defect in mood disorders.

“Thus, targeting Rac1 to moderate clinical symptoms (while there is potential for a translational approach there) has to be done very carefully, given the broad role of Rac1 in many cellular functions involving the actin cytoskeleton,” said Dr. Tejada-Simon, assistant professor of pharmacology and adjunct assistant professor of biology and psychology at University of Houston College of Pharmacy in Texas.

“The highlight of this research is in identifying a possible mechanism by which we can study pathways that are involved in remodeling of the brain; we might be able to find something a little bit more specific down the line,” Dr. Dietz said.

He noted that Rac1 has also been linked to addiction.

“It’s well known that there is comorbidity between depression and addiction, that one may lead to the other, so there seems to be something fundamentally related between Rac1 and these 2 psychiatric disease states.”

The research was supported by the National Institute of Mental Health and the Johnson and Johnson International Mental Health Research Organization Rising Star Award (presented to Dr. Russo). The other authors, Dr. Tejada-Simon, and Dr. Dietz have disclosed no relevant financial relationships.

Nat Med. Published online February 17, 2013. Abstract

Retrieved from: http://www.medscape.com/viewarticle/779544?src=nl_topic

Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression

Sam A Golden, Daniel J Christoffel, Mitra Heshmati, Georgia E Hodes, Jane Magida,Keithara Davis, Michael E Cahill, Caroline Dias, Efrain Ribeiro, Jessica L Ables, Pamela J Kennedy, Alfred J Robison, Javier Gonzalez-Maeso, Rachael L Neve, Gustavo Turecki, Subroto Ghose, Carol A TammingaScott J Russo

Nature Medicine(2013) doi:10.1038/nm.3090; Received 11 October 2012.  Accepted 14 January 2013.  Published online 17 February 2013.


Depression induces structural and functional synaptic plasticity in brain reward circuits, although the mechanisms promoting these changes and their relevance to behavioral outcomes are unknown. Transcriptional profiling of the nucleus accumbens (NAc) for Rho GTPase–related genes, which are known regulators of synaptic structure, revealed a sustained reduction in RAS-related C3 botulinum toxin substrate 1 (Rac1) expression after chronic social defeat stress. This was associated with a repressive chromatin state surrounding the proximal promoter of Rac1. Inhibition of class 1 histone deacetylases (HDACs) with MS-275 rescued both the decrease in Rac1 transcription after social defeat stress and depression-related behavior, such as social avoidance. We found a similar repressive chromatin state surrounding the RAC1 promoter in the NAc of subjects with depression, which corresponded with reduced RAC1 transcription. Viral-mediated reduction of Rac1 expression or inhibition of Rac1 activity in the NAc increases social defeat–induced social avoidance and anhedonia in mice. Chronic social defeat stress induces the formation of stubby excitatory spines through a Rac1-dependent mechanism involving the redistribution of synaptic cofilin, an actin-severing protein downstream of Rac1. Overexpression of constitutively active Rac1 in the NAc of mice after chronic social defeat stress reverses depression-related behaviors and prunes stubby spines. Taken together, our data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors.

Retrieved from: http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.3090.html

questions in genomic medicine…

In Genes, Genomic Medicine on Wednesday, 31 October 2012 at 15:12

Whole Genomes, Small Children, Big Questions

Jeantine E Lunshof

Personalized Medicine. 2012;9(7):667-669. © 2012  Future Medicine Ltd.


Whole-genome sequencing (WGS) is entering clinical practice. Expectations are high: a better understanding of disease, more accurate diagnosis and targeted therapies are hoped for; however, while some answers are being found, many new questions are arising. At the current stage, the dimensions of the -omics data sets in particular are overwhelming and physician–researchers are just starting to explore the ways in which they can be used. Apart from the bioinformatics challenges of genome data management there are the questions of meaningful interpretation of the emerging knowledge for health information users, both patients and professionals. At the individual and the societal level, questions are being asked about the extent and the usefulness of the newly available knowledge, for example: do whole-genome or -exome sequences tell us more than we want to know about ourselves, and doctors more than they need to know to treat their patients? In addition, do whole genomes tell parents more than they should know about their children? Since the early days of cytogenetic diagnosis, similar questions have been raised about the extent of the information yielded by testing, the communication of findings, and the ethical implications of testing.[1] Today, the availability of WGS and whole-exome sequencing (WES) for clinical diagnostics puts these old questions in a new context. Most recently, the feasibility of WGS was described for the application of noninvasive prenatal diagnosis.[2]

Diagnostics of Last Resort

WES and WGS are not routine diagnostic tools yet. However, while the introduction into the clinic of methods that are promising in the research setting is notoriously slow and usually accompanied by lengthy deliberations, medical emergencies can sometimes accelerate the process: a therapy of last resort that saves the life of an individual patient, may lead to a breakthrough in general clinical application. One striking example is the application of WES, coupled with meticulous bioinformatics analysis, that in a grand multidisciplinary effort saved the life of a little boy.[3]

The child was first seen at the age of 15 months presenting with an unusual, severe and progressive Crohn’s disease-like illness. A definitive diagnosis could not be made, restricting effective clinical management. The boy underwent more than 100 surgical procedures over 3 years. A hematopoietic progenitor cell transplant, that might be a therapy of last resort, was considered too risky without a clear diagnosis of the underlying disorder. Established genetic tests for known congenital immune disorders presenting with inflammatory bowel disease-like illness were not informative. Ultimately, with institutional review board approval, research-stage, nonvalidated, WES was performed to make a clinical diagnosis and guide the treatment decision. The identification of the causative mutation enabled treatment of the underlying immune disorder and of the child’s bowel disease as well.[3]

In a commentary article, alongside with the report describing the clinical and methodological details of the case, the Wisconsin group presents their ethical deliberations.[4] The authors raise some crucial questions – notwithstanding the impressive outcome and the indisputable huge benefit to the young patient – and suggest further discussion. This editorial aims to follow up on their suggestions.

The first issue raised is about the elusive boundary between research and clinical care. As this case shows, therapies of last resort can be considered a type of n = 1 studies and this is relevant from a regulatory point of view. n = 1 studies connect the bedside and the bench in a very specific and direct way.[5,6]

The other major issue, identified as an intrinsic concern by the Wisconsin group, is concerned with the data flood that results from WGS and WES and that greatly exceeds actual clinical needs. Inevitably, much of this information is ‘off target’ and may predict risks for late-onset disorders, which is considered particularly problematic when the genome analysis is performed in children.

Research & Clinical Care

Clinical application of research-stage procedures can save lives, as the exemplary case of the 15-month-old boy shows. In this case, the institutional review board-approved the use of nonvalidated experimental methods precisely because the primary purpose was to obtain a diagnosis for a patient; had the aim been gaining generalizable knowledge this would have turned it formally into research.[4] This reasoning, however, is based on a questionable and probably outdated distinction between research and clinical care that takes systematic recording of outcomes as the decisive criterion for research.[5,6] Moreover, can there be any instance of a diagnostic or therapeutic procedure – experimental or routine – that does not record results or yield generalizable knowledge? Also, clinical care and n = 1 studies are essentially connected. One could say that in ‘personalized’ medicine – and good medicine is always personalized – every medical intervention in an individual is a type of n = 1 study. The results from regular clinical care, however, will often hide in the patient’s medical record and potential new knowledge of general interest will remain with the attending physician unless so striking that it is shared through publication.

Revising the distinction between research and clinical care is urgent, now that WGS begins to enter the clinic.[7–9] For the development of personalized genomic medicine, a modified n = 1 study design is needed that enables resolving the old dichotomy and that also takes the normative (i.e., ethical and legal) aspects into account, as well as the translation in terms of health technology assessment.[5,6,10]

Small Children, Whole Genomes: Too Much Information?

The other key issue concerns the amount and extent of the data generated through WGS or WES: do we get too much information? And, what makes information too much?

One very simple answer to the latter question is that how much we need to know is determined by the problem that the sequencing was intended to solve. That problem seems to be clear at least in a clinical context, as the question there is: what is causing this disease in this patient, what is the actual diagnosis? This was actually the question the medical team in Wisconsin asked, desperate to know the cause of ther patient’s symptoms and to be able to make a diagnosis. Indeed, for their acute clinical purpose, the information about the XIAP deficiency was sufficient to balance potential harms and benefits of a risky intervention and to make a rational treatment decision. At this point, any further information from the patient’s exome could be regarded as redundant – ‘off target’ in the traditional clinical context.

In the context of systems biology-based medicine it is much harder to declare data as redundant or ‘off target’: the disease state of an individual results from particular network perturbations, and many known and unknown interactions between network components can play a role.[11] The interpretation is the problem, rather than the amount of data. Thus, information that may seem redundant today may later be found to be essential for a correct understanding of a disorder. For example, WGS data may contain clues about modifier genes (or non-coding RNAs)that seem of minor importance, but whose products do affect the disease phenotype.

Yet, the big question of how to handle the comprehensive genome information is still in the room, in the clinical context as well as in the research setting: what to communicate to patients, or to research participants? When children are concerned, the communication includes the parents and, depending on their age, the children themselves. From the ethical, legal and psychological point of view, WGS/WES in children is particularly interesting because areas of long-standing hot debate converge: children as research participants, genetic testing in children for clinical purposes, returning results to patients/study participants, and the major issue of generating predictive information.[12] The common denominator in these debates is the issue of data access and sharing information – in particular the sharing with the true data owners, namely, the participants, patients and with parents as caretakers. However, parents’ entitlement to access all of their child’s data is not undisputed, as it could be seen as a breach of the child’s privacy.[12] The inherent lack of informed consent – depending on age and maturity – for clinical interventions and research participation presents a major and unavoidable dilemma for which no generally valid solution exists.

On the Horizon: New Methods, Old Questions

In their commentary, the group from Wisconsin present the outline of a plan for returning results to parents that shall allow the parents to decide what type of ‘off-target’ information they want to receive.[4] Other researchers recently found in a focus group study among parents of children with serious conditions that these parents wished to receive all types of research results, not only those that would be actionable.[13] The early application of WGS/WES for solving clinical puzzles has shown great therapeutic benefit for a number of children with serious conditions.[7] Similar to the case of the young child described above, the stories about these children were not only published in scholarly journals but also fully disclosed in the general media.[101,102]

Beyond the clinical applications, WGS greatly advances more fundamental research, as demonstrated by the Pediatric Cancer Genome Project.[14]

New applications of WGS are on the horizon, even if they are not around the just corner yet. Noninvasive prenatal diagnosis through WGS is technically feasible.[2] The genome of a fetus was successfully predicted, based on inferences made from the genome of the mother, the father and the estimated fetal proportion of the cell-free DNA in the mother’s circulation. However, this was no more than a proof-of-principle at the moment, and the major technical difficulty in the future will be the data interpretation, as the authors conclude.

On the nontechnical side, however, the difficulties could be even bigger, as a decades-old debate on some deep and unsolvable moral issues in prenatal diagnosis will be rejuvenated.

Retrieved from: http://www.medscape.com/viewarticle/771374?src=nl_topic


  1. Hsu LY, Durbin EC, Kerenyi T, Hirschhorn K. Results and pitfalls in prenatal genetic diagnosis. J. Med. Genet.10,112–119 (1973).
  2. Kitzman JO, Snyder MW, Ventura M et al. Noninvasive whole-genome sequencing of a human fetus. Sci. Transl Med.4(137),137ra76 (2012).
  3. Worthey EA, Mayer AN, Syverson GD et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet. Med.13(3),255–262 (2011).
  4. Mayer AN, Dimmock DP, Arca MJ et al. A timely arrival for genomic medicine. Genet. Med.13(3),195–196 (2011).
  5. Tsapas A, Matthews DR. Using n-of-1 trials in evidence-based clinical practice. JAMA301(10),1022–1023 (2009).
  6. Chalmers I. Regulation of therapeutic research is compromising the interests of patients. Int. J. Pharm. Med.21(6),395–404 (2007).
  7. Bainbridge MN, Wiszniewski W, Murdock DR et al. Whole-genome sequencing for optimized patient management. Sci. Transl Med.3(87),87re3 (2011).
  8. Dixon-Salazar TJ, Silhavy JL, Udpa N et al. Exome sequencing can improve diagnosis and alter patient management. Sci. Transl Med.4(138),138ra78 (2012).
  9. Check Hayden E. Sequencing set to alter clinical landscape. Nature482,288 (2012).
  10. Becla L, Lunshof JE, Gurwitz D et al. Health technology assessment in the era of personalized health care. Int. J. Technol. Assess. Health Care27(2),118–126 (2011).
  11. Vidal M, Cusick ME, Barabási AL. Interactome networks and human disease. Cell144,986–998 (2011).
  12. Mand C, Gillam L, Delatycki MB, Duncan RE. Predictive genetic testing in monors for late onset conditions: a chronological and analytical review of the ethical arguments. J. Med. Ethics doi:10.1136/medethics-2011-100055 (2012) (Epub ahead of print).
  13. Harris ED, Ziniel SI, Amatruda JG et al. The beliefs, motivations, and expectations of parents who have enrolled their children in a genetic biorepository. Genet. Med.14(3),330–337 (2012).
  14. Downing JR, Wilson RK, Zhang J et al. The pediatric cancer genome project. Nat. Genet.44(6),619–622 (2012).

    101. One In A Billion: A boy’s life, a medical mystery. http://www.jsonline.com/features/health/111224104.html
    102. Genome Maps Solve Medical Mystery For Calif. Twins. http://www.npr.org/blogs/health/2011/06/18/137204964/genome-maps-solve-medical-mystery-for-calif-twins

autism and schizophrenia…kissing cousins.

In Autism Spectrum Disorders, Genes, Genomic Medicine, Neuroscience on Thursday, 25 October 2012 at 16:29


Are autism and schizophrenia related?

Posted on October 23, 2012 by Stone Hearth News

Autism Spectrum Disorders (ASD), a category that includes autism, Asperger Syndrome, and Pervasive Developmental Disorder, are characterized by difficulty with social interaction and communication, or repetitive behaviors. The U.S. Centers for Disease Control and Management says that one in 88 children in the US is somewhere on the Autism spectrum — an alarming ten-fold increase in the last four decades.

New research by Dr. Mark Weiser of Tel Aviv University’s Sackler Faculty of Medicine and the Sheba Medical Center has revealed that ASD appears share a root cause with other mental illnesses, including schizophrenia and bipolar disorder. At first glance, schizophrenia and autism may look like completely different illnesses, he says. But closer inspection reveals many common traits, including social and cognitive dysfunction and a decreased ability to lead normal lives and function in the real world.

Studying extensive databases in Israel and Sweden, the researchers discovered that the two illnesses had a genetic link, representing a heightened risk within families. They found that people who have a schizophrenic sibling are 12 times more likely to have autism than those with no schizophrenia in the family. The presence of bipolar disorder in a sibling showed a similar pattern of association, but to a lesser degree.

A scientific leap forward, this study sheds new light on the genetics of these disorders. The results will help scientists better understand the genetics of mental illness, says Dr. Weiser, and may prove to be a fruitful direction for future research. The findings have been published in the Archives of General Psychiatry.

All in the family

Researchers used three data sets, one in Israel and two in Sweden, to determine the familial connection between schizophrenia and autism. The Israeli database alone, used under the auspices of the ethics committees of both the Sheba Medical Center and the Israeli Defense Forces, included anonymous information about more than a million soldiers, including patients with schizophrenia and ASD.

“We found the same results in all three data sets,” he says, noting that the ability to replicate the findings across these extensive databases is what makes this study so significant.

Understanding this genetic connection could be a missing link, Dr. Weiser says, and provides a fresh direction for study. The researchers are now taking this research in a clinical direction. For now, though, the findings shouldn’t influence the way that doctors treat patients with either illness, he adds.

Retrieved from: http://www.stonehearthnewsletters.com/are-autism-and-schizophrenia-related/autism/

genes, genes, genes…more awesomeness in genomic medicine!

In Autism Spectrum Disorders, Genes, Genomic Medicine, Neuroscience on Thursday, 25 October 2012 at 14:26


Multiple papers recently published have documented links between de novo mutations and autism, schizophrenia, and intellectual disability. Here, I review the topic and raise some of the key questions on this issue going forward.

– Kong A, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488:471-475.
– Wang J, et al. Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm. Cell. 2012;150:402-412.
– Rauch A, et al. Range of genetic mutations associated with severe non-syndromic intellectual disability: an exome sequencing study. Lancet. 2012 Sept 26. [Epub ahead of print]
– de Ligt J, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Oct 3. [Epub ahead of print]


Below is a transcript of Dr. Topol’s post “De Novo Mutations and the Implications for the Father’s Biological Clock.” We look forward to your feedback.
Our topic is de novo mutations and the implication of these new mutations for expectant fathers. This is a really important topic that was highlighted by the cover article in August 2012 in Nature. It was also in recent multiple papers in Cell, where sperm was sequenced for the first time, as well as in multiple papers on de novo mutations in Nature and Nature Genetics.

While we have known about the possibility for new mutations to occur that are not heritable, the quantification of this has become possible now that we can do sequencing of sperm and compare that to the germline DNA of the father. What is fascinating is that there have been now multiple papers that have come out in recent weeks to demonstrate the link between de novo mutations and intellectual disability, schizophrenia, and autism — and especially the paper coming from the Icelandic group DECODE, which linked the father’s age with the incidence of de novo mutations.

These new mutations are not frequent, of course, but if there’s just one per exome, that is, throughout the coding elements of the genome, that can be quite damaging. In fact, it is characteristic of de novo mutations that they tend to be bad and have adverse consequences.

While there are many more in a typical genome, somewhere around 70 or more of various types of mutations, whether they’re single nucleotide polymorphisms or insertions/deletions, most of them do not fall in protein coding elements. But when they do, the data we have so far from this collective work suggest that they can be damaging.

The big issue going forward is — what can we do about this? Is this de novo mutation related to our environment? Can we try to reduce the age of fathers and set up the “male biological clock,” which, for all of the years, has been largely restricted to the mother’s story? Can we someday screen sperm for de novo mutations, screen them out or at least get a sense of the frequency? It seems unlikely that we would sequence and then use the sperm for in vitro fertilization, but perhaps we can leverage this knowledge. Of course, the age relationship is tricky because, so far, we don’t have much data to suggest an age range, but clearly there is a relationship with age of the father as it extends to 40 and beyond with a higher rate of de novo mutations.

We also know that, concurrently, the rate of diagnosis of autism is increasing. Could this have something to do with this de novo mutation increase and the overall trend of a higher paternal age?

There is a lot here to consider on a theme that is showing up in multiple papers: the way to quantify de novo mutations, understand their increased frequency as fathers age, and this very interesting link to multiple neurologic, neurocognitive, and neuropsychiatric conditions.

Over time, it’s likely that these de novo mutations will exert a phenotype that is beyond the neurology world. It will also be interesting to see how de novo mutations could potentially have a beneficial role. But one thing for sure is that this is part of the story about missing heritability: we couldn’t account for things that were happening in a new generation that were not present from the parents, and de novo mutations are certainly a part of that story.

Thanks for your attention. I look forward to your comments about de novo mutations and especially the father’s biological clock phenomenon.

Retrieved from: http://boards.medscape.com/forums?128@410.Oln9aayNn1L@.2a35a68e!comment=1

Treating autism with a supplement? New research says yes.

In Autism Spectrum Disorders, Genes, Genomic Medicine on Sunday, 7 October 2012 at 07:18

New Form of Autism May Be Treatable With Supplement

Pam Harrison

October 1, 2012 — A homozygous mutation that silences the gene involved in the metabolism of branched-chain amino acids (BCAAs) has been identified in a group of children who have autism and either epilepsy or abnormalities on electroencephalogram (EEG), an international team of investigators has reported.

Gaia Novarino, PhD, from the University of California, San Diego, and multicenter colleagues identified a mutation in the branched-chain ketoacid dehydrogenase kinase (BCKDK) gene in families among whom parents were cousins and whose children had autism, epilepsy, and intellectual disability.

“The normal role of the BCKDK gene is to shut off the metabolism of the BCAAs,” coauthor Joseph Gleeson, MD, University of California, San Diego, told Medscape Medical News. “And the end result of these mutations is hypermetabolism of the BCAAs and their depletion in patients who carry them.”

In mice, the researchers were able to show that a BCAA-enriched diet abolished the neurologic deficits within a week.

The study was published online September 6 in Science.

Related Families

As Dr. Gleeson noted, investigators set out specifically to study families in which parents were related to each other to allow them to identify recessive causes of disease.

They identified 2 consanguineous families, one of Turkish descent and a second of Egyptian ancestry, in which children had autism, intellectual disability, and either seizure or abnormal electroencephalograms (EEGs). Whole-exome sequencing was carried out in both families.

Researchers focused on the identification of homozygous variants that were predicted to result in loss of protein function, which would be consistent with the presumed mode of recessive inheritance.

“In each of these families, we identified a distinct, null, homozygous mutation in the [BCKDK] gene,” investigators write, “and no other homozygous loss-of-function mutations segregating with affected status were identified in either family.”

Investigators also studied the effect of a chow diet containing 2% BCAAs or a BCAA-enriched diet, consisting of 7% BCAAs, on Bckdk mice deficient in the same gene. These mice have reduced levels of BCAAs in various tissues.

“Mice raised on the BCAA-enriched diet were phenotypically normal,” the authors observed, “[whereas] on the 2% BCAA diet…Bckdk mice and not wildtype had clear neurological abnormalities such as seizures…that appeared within 4 days of instituting the 2% BCAA diet.”

The same neurologic deficits were completely abolished within a week of the same mice starting the BCAA-enriched diet, suggesting that Bckdk mice have an inducible yet reversible phenotype.

“What was really surprising to us is that the children [we studied] could have come into any autism clinic because they looked like any child with autism, there was no way to differentiate them clinically,” Dr. Gleeson said. “The only way we were able to make the discovery was by sequencing the DNA, which was where we found the mutation.”

Dr. Gleeson added, too, that it was “very surprising” to find mutations in a potentially treatable metabolic pathway specific for autism, namely through BCAAs supplementation in patients with this specific mutation.

Investigators would welcome any parents whose children have the same constellation of autism with accompanying epilepsy or EEG abnormalities into their screening program.

Translation Medicine

Valerie Hu, PhD, from George Washington University, Washington, DC, told Medscape Medical News that she liked how the study translated novel genetic findings from exome sequencing to a functional/biochemical phenotype, demonstrating reversibility in the mouse model through nutritional supplementation.

“I think that recent research in the field is really opening up new horizons,” she added.

Dr. Hu is herself pursuing research related to the genetic underpinnings of autism.

The study was funded in part by the National Institutes of Health. Dr. Gleeson and his co-investigators have filed for a patent on the genetic diagnosis and potential treatment of this particular form of autism. Dr. Hu has no disclosed no relevant financial relationships.

Science. Published online September 6, 2012. Abstract

Retrieved from: http://www.medscape.com/viewarticle/771886?src=nl_topic

Noninvasive Prenatal Diagnosis: Can Ethics and Science Meet?

In Genes, Genomic Medicine, Neuropsychology, Neuroscience on Wednesday, 26 September 2012 at 07:30

posting as an addition to my recent post on genomic medicine.  the growing field and research in genomic medicine raises some interesting ethical issues.

Noninvasive Prenatal Diagnosis: Can Ethics and Science Meet?

Elizabeth H. Dorfman; Mildred Cho, PhD

Editor’s Note:
Technological advances have enabled researchers to sequence an entire fetal genome noninvasively by extracting cell-free fetal DNA from maternal plasma.[1,2] This use of noninvasive prenatal diagnosis (NIPD) shifts the focus away from screening for known or suspected anomalies and inherited conditions to potentially discovering a wide array of information about the fetus that patients and clinicians might not be prepared to address.

On behalf of Medscape, Elizabeth H. Dorfman, a graduate student at the University of Washington Institute for Public Health Genetics, Seattle, Washington, interviewed Mildred Cho, PhD, Professor at the Stanford Center for Biomedical Ethics, Stanford, California, about the ethical and social implications of NIPD and how advances in these techniques might affect clinical practice.

Ms. Dorfman: Let’s start with a few background questions to set the stage. Can you briefly describe the technique behind NIPD using cell-free fetal DNA?

Dr. Cho: NIPD allows prenatal testing to be done from a sample of maternal blood instead of having to take a sample through invasive techniques, such as amniocentesis or chorionic villus sampling. There are a lot of different ways of analyzing fetal DNA in maternal serum; this technology, which is more recently developed, enables one to look at fragments of cell-free fetal DNA as opposed to fetal cells in maternal blood.

Ms. Dorfman: In regard to the timing of testing, risk to the fetus or the pregnancy, or potential for incidental findings — are they substantively different for NIPD compared with existing tests, or are they similar?

Dr. Cho: NIPD could potentially be used earlier in gestation, so that would give people more time to think about what to do with the results. Right now, I don’t think it’s being used very early because the ability to get enough DNA in the sample hasn’t been worked out fully, but that is the hope. Obviously, because it’s noninvasive, that makes a big difference to the person who is giving the sample: Not only is it not uncomfortable or painful, but there is virtually no risk to the fetus from taking the sample.

Ms. Dorfman: A team at the University of Washington recently announced that they had used noninvasive cell-free fetal DNA methods to sequence the entire genome of a developing fetus.[1] Could you go into a little bit of detail about how this changes the scope of NIPD?

Dr. Cho: Currently, fetal testing is done either to screen for one of a small number of conditions, or as follow-up to a prior screening, such as a genetic screening or fetal ultrasonography. In these cases, the fetal diagnostic test will be used to focus on any conditions or anomalies that turned up positive in the prior screen, or to detect a condition that is of particular concern that may have been identified through a family history. So, diagnostic testing will be just that: diagnostic, trying to come up with a genetic cause for an observed or suspected anomaly.

When or if it becomes possible to do whole-genome analysis in a clinical setting routinely, it will open up the possibility that people can get information about the fetus that is well beyond a handful of known fetal conditions, such as a trisomy. This raises the concern that people will be faced with a huge amount of information about which there might be a lot of uncertainty and will have very little time to consider what to do with the information.

Thinking even further into the future, one of the concerns is that it could potentially change the way people think about pregnancy because it might be perceived that they have a lot of choices to make about what kind of children they want to have. Moving from a limited set of conditions to potentially any kind of human trait that has a major genetic component could really change the way people think about pregnancy and prenatal testing.

Ms. Dorfman: How does this potentially expanded capability reconcile with current practice guidelines and policy statements related to genetic testing in children? For example, the American Academy of Pediatrics Committee on Genetics’ recommendations on ethical issues with genetic testing in pediatrics,[3] or the National Society of Genetic Counselors’ position statements on prenatal and childhood testing for adult-onset disorders.[4]

Dr. Cho: There is going to have to be some further thought about how this kind of fetal testing might be used by clinicians. The current guidelines don’t really speak to whether there are professional limits on what clinicians will and will not use genetic testing for, so the clinical communities will have to ask themselves whether there are any genetic traits for which they won’t offer testing, or whether there are any limits on information that they will provide to patients.

Ms. Dorfman: As a follow-up to that, the editor’s summary of the University of Washington study that was published in Science Translational Medicine [1] stated, “An ideal prenatal genetic diagnostic would noninvasively screen for all Mendelian disorders early in pregnancy.” I was wondering whether you agreed with or had any comments about that statement.

Dr. Cho: We have to think about what “ideal” means to different people. We can currently test for a lot of mendelian conditions, and yet a lot of people don’t opt to get those tests. For a lot of people, that kind of information might be unwanted; some of it may be the kind of information that won’t have any bearing on how people treat their pregnancies, or it may not be relevant until after the child is born. I think that’s something that can be debated, whether that’s an ideal situation or not.

Ms. Dorfman: NIPD requires a blood sample from the pregnant woman, and as you have described, carries no risk for miscarriage or direct fetal harm. Of note, this has raised concerns about inadequate informed consent, and I was hoping that you can comment on where this concern came from.

Dr. Cho: People who are already familiar with prenatal screening tests that analyze maternal serum already know that sometimes, women may not realize that one of the blood samples taken during pregnancy was not used to check their blood glucose, but was actually a prenatal screening test. So I think the concern is that if there isn’t a specific and unique procedure that is part of the prenatal testing process, it could go almost unnoticed until the results come back — and then be a shock to people who get the results. They might not understand the implications of this type of testing.

Ms. Dorfman: Is there consensus about the information and risks that should be disclosed in the informed consent process before NIPD?

Dr. Cho: I don’t think there is consensus on how to deal with information that should be disclosed in almost any clinical situation, and no, I don’t think that there is consensus for how to deal with genomic results and NIPD.

Ms. Dorfman: What risks do you think should be disclosed before testing?

Dr. Cho: People should understand that a prenatal test is being done and that the information they might receive from that test could be very broad and potentially have a major impact on decision-making. And if they have a choice to not get all that information, they should understand that as well.

The consent process should note the risk for getting information that the person might not want, and also that the information might affect family members as well, who may not be interested in getting genomic information.

Ms. Dorfman: Noninvasive testing using cell-free fetal DNA can be used to determine fetal gender as early as 7 weeks’ gestation. Is there any reason to think that this will promote prenatal sex selection in regions where this has not been a problem or exacerbate the practice in regions where this is already a concern?

Ms. Cho: There might be reason to be concerned about the use of cell-free fetal DNA testing for sex selection, especially in areas where gender imbalance is already widespread. Even if there are laws against sex selection, it would be relatively easy to get a blood sample and also relatively easy to send it out of the country, and to get a result back.

It’s something to be aware of and keep tabs on. Companies that offer testing will have to think about how they’re going to determine whether the samples are being used for things that are actually illegal in other countries; it may be their obligation to ensure that they’re not contributing to illegal behavior.

Ms. Dorfman: The American College of Obstetrics and Gynecology has published a position statement that this new technology should not be used for the purposes of sex selection.[5] Do you have any recommendations on what, if anything, should be done proactively to prevent that from becoming an issue in such countries as the United States, where we don’t see this as an issue but where we also don’t have laws banning it?

Dr. Cho: There is a professional stance against sex testing in the United States. But in places where sex testing is not necessarily against professional guidelines or is illegal, there needs to be more thought about what responsibility the testing companies have and what practical measures laboratories can take to ensure that they’re not potentially violating the law.

Ms. Dorfman: There is significant interest in whether and when to return genetic results to patients. How does this take shape in NIPD?

Dr. Cho: This question of returning results of genomic findings may be even more important in prenatal testing than in other clinical situations. In prenatal settings, patients typically have very broad autonomy to make decisions about what kind of information they seek and about what kind of information they have access to. It’s a little different from returning results in, say, adult medicine where you could argue that genomic results shouldn’t be treated any differently from other kinds of medical testing. But in the prenatal setting, there is usually such a premium put on autonomy of the patient to make decisions about her pregnancy that it puts the issue of returning results in a bit of a different light.

Ms. Dorfman: Noninvasive methods that require both a maternal and a paternal sample to determine which of the DNA segments are from the fetus could introduce additional opportunities for incidental findings. Could you comment on that?

Dr. Cho: I agree; when you’re getting samples from the mother and the father, you definitely have a much greater potential for incidental findings. It should be part of the consent process and their understanding of what kind of results they may potentially get back.

Ms. Dorfman: What efforts are currently under way to characterize how NIPD is affecting clinical practice and reproductive decision-making, if any?

Dr. Cho: Some people are studying the clinical implementation of NIPD, which is currently limited to aneuploidy detection. I don’t know that it’s being studied broadly for applications other than aneuploidy at this point, but I imagine that will happen in the near future.

A side issue that might become influential in the application of cell-free fetal DNA research to clinical practice is the question of intellectual property and whether patents for cell-free fetal DNA testing might affect how clinicians can or cannot use the test. The ethical side of this is how or whether intellectual property policy should be allowed to dictate how clinical tests are or are not available to clinicians and patients.

Ms. Dorfman: Looking ahead, how do you think can we best maximize the benefits of cell-free fetal DNA testing capabilities while minimizing the potential harm? Are there regulations or policies that can be implemented that you think would yield a favorable balance of risks and benefits?

Dr. Cho: That’s a good question, but I don’t have a very good answer. Some of the concerns about potentially eugenic uses of cell-free fetal DNA in a prenatal setting are very difficult to address at the policy level, and we haven’t done a very good job of that so far with other kinds of prenatal testing. A lot will depend on such things as informed consent, which has not proven very effective right now for other types of prenatal testing, so it is likely going to be a difficult problem to tackle.

The US Food and Drug Administration might be more willing to regulate this kind of genetic testing than other kinds of genetic testing simply because the nature of the decisions made in the prenatal setting are so much more ethically fraught and important. More specific scrutiny of prenatal genetic testing, putting into play some kind of mechanism for quality control, quality assessment, and accuracy at an analytic level would at least help to minimize some of the risks from having inaccurate results.

But the large social and ethical issues are going to be very difficult to address through policy, and clinicians are going to have a hard time dealing with them. Up to this point, we’ve been very reluctant to interfere with prenatal decision-making. Much of this will probably end up being left to public education efforts, which may be of limited effectiveness.


  1. Kitzman JO, Snyder MW, Ventura M, et al. Noninvasive whole-genome sequencing of a human fetus. Sci Transl Med. 2012;4:137ra76.
  2. Fan HC, Gu W, Wang J, Blumenfeld YJ, El-Sayed YY, Quake SR. Non-invasive prenatal measurement of the fetal genome. Nature. 2012;487:320-324. Abstract
  3. Committee on Bioethics. Ethical issues with genetic testing in pediatrics. Pediatrics. 2001;107:1451-1455. Abstract
  4. National Society of Genetic Counselors. Position Statement: Prenatal and Childhood Testing for Adult-onset Disorders. 1995. http://www.nsgc.org/Advocacy/PositionStatements/tabid/107/Default.aspx#PrenatalChildTestingAdultOnsetAccessed July 12, 2012.
  5. American College of Obstetrics and Gynecology. ACOG Committee Opinion: Sex Selection; February 2007 (reaffirmed 2011). http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Ethics/Sex_SelectionAccessed July 12, 2012.

Medscape Genomic Medicine © 2012 WebMD, LLC

Retrieved from: http://www.medscape.com/viewarticle/771190?src=nl_topic


First Direct Genetic Evidence for ADHD Discovered-2010

In ADHD, ADHD Adult, ADHD child/adolescent, Genes, Genomic Medicine, Neuropsychology, Psychiatry, School Psychology on Tuesday, 25 September 2012 at 06:20

an older article, but one i thought worthy of posting.

First Direct Genetic Evidence for ADHD Discovered

Caroline Cassels

September 29, 2010 — New research provides the first direct evidence that attention-deficit/hyperactivity disorder (ADHD) is genetic.

In a study published online September 30 in The Lancet, investigators from the University of Cardiff in the United Kingdom say their findings, which show that ADHD has a genetic basis, suggest it should be classified as a neurodevelopmental and not a behavioral disorder.

“We’ve known for many years that ADHD may well be genetic because it tends to run in families in many instances. What is really exciting now is that we’ve found the first direct genetic link to ADHD,” principal investigator Anita Thapar, MD, told reporters attending a press conference to unveil the study results.

In the genomewide analysis, 366 children 5 to 17 years of age who met diagnostic criteria for ADHD but not schizophrenia or autism and 1047 matched controls without the condition were included. Researchers found that compared with the control group without ADHD, children with the disorder were twice as likely — approximately 15% vs 7% — to have copy number variants (CNVs).

CNVs, explained study investigator Nigel M. Williams, PhD, are sections of the genome in which there are variations from the usual 2 copies of each chromosome, such that some individuals will carry just 1 (a deletion) and others will have 3 or more (duplications).

“If a gene is included in one of these copy number variants, it can have deleterious consequences,” said Dr. Williams.

Shared Biological Link

The study authors note that the increased rate of CNVs was particularly high among children with a combination of ADHD and learning disabilities but “there was also a significant excess in cases with no such disability.”

The researchers also found that CNVs overlap with chromosomal regions that have previously been linked to autism and schizophrenia. Although these disorders are thought to be completely separate, there is some overlap between ADHD and autism in terms of symptoms and learning difficulties.

We’ve looked at only 1 class of variation, but it’s an important one because it has been linked to other brain disorders.

This finding suggests there may be a shared biological basis for the 2 conditions and, according to investigators, provides the first direct evidence that ADHD is a neurodevelopmental condition.

“We found that the most significant excess of these types of copy number variants was on a specific region of chromosome 16. This chromosomal region includes a number of genes, including one that affects brain development,” said Dr. Thapar.

The team’s research marks the start of the “unraveling of the genetics” of ADHD, according to Dr. Thapar.

“We’ve looked at only 1 class of variation, but it’s an important one because it has been linked to other brain disorders,” she said.

Implications for DSM-5?

Dr. Thapar added that the study results also have direct implications for the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), which is currently under development by the American Psychiatric Association.

A “huge debate” about whether ADHD should be classified as a behavioral or neurodevelopmental disorder is ongoing. However, she said, these findings should help put this controversy to rest.

“Our results clearly show that ADHD should be considered a neurodevelopmental disorder,” she said.

In fact, Dr. Thapar noted that the study findings have been submitted to one of the DSM-5 work groups for consideration in the development of the new manual.

The investigators note that despite epidemiologic evidence derived from twin studies showing high heritability and the fact that ADHD is often accompanied by learning disabilities, there is still a great deal of public misunderstanding about the disorder.

Some people say this is not a real disorder, that it is the result of bad parenting. Children and parents can encounter much stigma because of this. So this finding of a direct genetic link to ADHD should help clear this misunderstanding and help address the issue of stigma.

“Some people say this is not a real disorder, that it is the result of bad parenting. Children and parents can encounter much stigma because of this. So this finding of a direct genetic link to ADHD should help clear this misunderstanding and help address the issue of stigma,” said Dr. Thapar.

Although there are no immediate treatment implications, Dr. Thapar said she hopes the research will have an immediate impact in terms of shifting public perception about ADHD and fuel further research into the biological basis of the disorder with a view to developing better, more effective therapies for affected individuals.

In an accompanying editorial, Peter H. Burbach, PhD, from the Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, the Netherlands, writes, “The first gains beyond today’s study might be initial insights into the pathogenesis and neurobiology of brain development as influenced by these genetic variants. This knowledge will eventually enter the clinic and might affect the way people think about and treat neurodevelopmental disorders by accounting for the biological consequence of the specific patient’s genotype.”

Lancet. Published online September 30, 2010.

Retrieved from: http://www.medscape.com/viewarticle/729652

Genomic Medicine

In Genes, Genomic Medicine on Monday, 24 September 2012 at 16:20

how positively fascinating…

Genomic Medicine: Evolving Science, Evolving Ethics

Sarah E Soden; Emily G Farrow; Carol J Saunders; John D Lantos

Personalized Medicine. 2012;9(5):523-528. © 2012 Future Medicine Ltd.

Abstract and Introduction


Genomic medicine is rapidly evolving. Next-generation sequencing is changing the diagnostic paradigm by allowing genetic testing to be carried out more quickly, less expensively and with much higher resolution; pushing the envelope on existing moral norms and legal regulations. Early experience with implementation of next-generation sequencing to diagnose rare genetic conditions in symptomatic children suggests ways that genomic medicine might come to be used and some of the ethical issues that arise, impacting test design, patient selection, consent, sequencing analysis and communication of results. The ethical issues that arise from use of new technologies cannot be satisfactorily analyzed until they are understood and they cannot be understood until the technologies are deployed in the real world.


Genomic medicine is rapidly evolving and changing the ways in which we think about the ethical, legal and economic regulation of this powerful biotechnology.

Public perceptions of genetic testing are complex and ambivalent. They have been shaped by some of the more unsavory uses to which genetics has been put in the past. It is difficult to separate our thoughts about current genetic screening for medical care from practices such as the eugenics movement, racial profiling based upon faulty understandings of genetics and compulsory sterilization programs throughout Europe and north America.[1]

Past controversies about the appropriate use of genetic testing have led to many of the ethical and regulatory safeguards that surround genetic testing today. Genetic testing created a backlash due to it being used against people, rather than for them. Genetic testing came to be seen as fundamentally different from other forms of testing, one in need of more rigorous and explicit policies regarding informed consent and voluntariness.[2]

This genetic exceptionalism continues today; however, it is taking new forms. We still tend to treat genetic testing as if it is ethically and legally distinct from other sorts of testing. However, technological advances, particularly those that allow testing to be done quicker, less expensively and with much a higher resolution, are pushing the envelope on existing moral norms and legal regulations. Genetic testing is one of the first types of testing that is being offered directly to consumers. Today, one can send a sample of saliva to a direct-to-consumer genetic testing company and receive results about one’s risk factors for a variety of medical conditions. Often, the information is difficult to interpret, probabilistic and based on algorithms that are proprietary and thus somewhat mysterious. Still, genetic testing joins a relatively small group of other diagnostic tests, such as home pregnancy tests, blood pressure testing and glucometers in its ready availability to the consumer without a physician intermediary.

The day may be coming, and quite soon, when whole-genome or -exome sequencing will be readily available. It is hard to know whether to think of this as a good or a bad thing, whether people who undergo such testing – whether they are patients, research subjects or consumers – will be helped or harmed by it. In this article, we will speculate about the near future of genetic testing by analyzing the way such testing is used as a new and inexpensive way of diagnosing rare genetic conditions in symptomatic children.

Next-generation Sequencing for the Diagnosis of Rare Mendelian Conditions

One of the most difficult challenges facing pediatricians is that of diagnosing rare genetic conditions in children who present with signs and symptoms that suggest an underlying genetic cause, but for whom the etiology remains elusive despite costly and often lengthy etiologic investigations. Such cases arise commonly in clinics that evaluate children for, among other things, cognitive impairment, neuromuscular disorders and congenital anomalies.[3] Such diagnostic odysseys often include serial molecular testing of one or a few genes; a process that can be emotionally taxing to families and frustrating to physicians, who must decide together how long to pursue the quest for diagnosis.[4]

The advent of next-generation sequencing (NGS) coupled with advanced bioinformatic processing is changing this diagnostic paradigm. At Children’s Mercy Hospital in Kansas City (MO, USA), we have introduced a highly multiplexed molecular diagnostic test that enables simultaneous interrogation of genes associated with more than 500 X-linked, autosomal-recessive and mitochondrial-pediatric diseases, including some genes for which no commercially available molecular test exists.[5] Currently available on a research basis, this test is being offered to complex pediatric patients by subspecialists in our institution. As we move toward clinical implementation, it is projected that the cost will initially be less than that of a single conventional molecular test (<US$1000), and will continue to fall rapidly.[101] Furthermore, turnaround time will rival conventional molecular tests which commonly have a time-to-result of 2–8 weeks. Thus, NGS-based diagnostic testing will lower the threshold for physicians to pursue gene sequencing, and ultimately advance knowledge of the biologic underpinnings of challenging pediatric diseases.

Ethical considerations affect all aspects of the implementation of this program, including test design, patient selection, consent, sequencing analysis of patient DNA and delivery of results to patient and family. Potential unintended consequences of multiplexed genetic testing in children include: detection of carrier status for recessive diseases; and discovery of predisposition to adult onset disease. Conservative estimates are that humans carry at least ten recessive Mendelian diseases.[6] With the possible exceptions of cystic fibrosis and sickle cell disease, it is rare for individuals to have knowledge of the single recessive alleles residing in their genome. The American Society of Human Genetics (ASHG; MD, USA)/American College of Medical Genetics (ACMG; MD, USA) guidelines for genetic testing of minors prohibits predictive genetic testing for adult onset diseases and discourages reporting of carrier status to minors.[7] In all such testing, physicians and scientists should be concerned about violating the child’s right to what has been called ‘an open future’, that is, a future not involuntarily shaped by information of uncertain accuracy that the child did not ask for or necessarily want to know.

Informed Consent

Informed consent for NGS testing is complex. The 2012 ACMG policy statement on clinical application of genomic sequencing recommends pretest counseling with a medical geneticist or genetic counselor, and that formal consent should be a part of the process.[102] Specifically, patients must be informed of the expected results from testing, including the likelihood of incidental findings. A significant challenge to this process is the lack of a clear consensus in the genetics community on how incidental findings should be handled, especially in the pediatric population. Currently, each individual laboratory is responsible for determining how incidental findings will be handled and reported. Further complicating the process is the recommendation that patients be offered the option of not receiving results from secondary or incidental findings.

We have also encountered an additional layer of complexity in the consenting process at our institution. In our experience, some families with children suffering potentially fatal conditions and/or progressive disease ask very few questions when we explain gene sequencing and seek their consent. For parents, the urgency to help an ill child is paramount and overshadows potentially thorny issues such as discovery of their child’s (and potentially their own) carrier status or future disease risk. Our challenge then, is to build protections into the testing process. In our institution one such protection has been to develop a team of core users: 20 medical geneticists, pediatric subspecialists and genetic counselors who participated in test design and implementation policies. This process necessitated an uncommon understanding of genomic medicine including, but not limited to, knowledge of: ACMG/ASHG pediatric guidelines, the Genetic Information Nondiscrimination Act,[8] and the potential benefits and limitations of NGS. The goal is for these clinicians to become uniquely suited to offer this test to the appropriate patients and, in collaboration with knowledgeable genetic counselors, engage in a meaningful informed consent process with families.

Test Design & Interpretation

A unique patient protection strategy developed in our institution is Sign and Symptom Assisted Gene Analysis; a component of our bioinformatic pipeline that reduces the risk of violating ASHG guidelines by not identifying genetic findings unrelated to the patient’s presenting condition [Saunders CJ et al., Rapid whole genome sequencing for genetic disease diagnosis in neonatal intensive care units (2012), Manuscript in preparation]. Physician who order our NGS diagnostic panel are required to select up to ten clinical signs and symptoms from a controlled medical ontology of 225 terms. Sign and Symptom Assisted Gene Analysis generates a unique candidate gene list specific to that patient. Genes not on the candidate list are not analyzed computationally, thereby greatly reducing the likelihood of unintended findings such as carrier status or future disease risk unrelated to the child’s clinical condition.

Even with such protections, expert interpretation is necessary. For example, two very different conclusions may be made when a single heterozygous pathogenic variant in an autosomal recessive locus is detected. Such a finding may be inadvertent detection of carrier status in a child. However, it may also be diagnostic in the case of a compound heterozygote; such individuals may have a second undetectable variant derived from the other parent in the same gene but outside the sequenced region. A careful review of the literature, knowledge of the gene in question, phenotypic plausibility and genotyping of the parents must factor in the interpretation. The size of the candidate gene list also impacts interpretation of such a case. A single pathogenic variant is more likely to be thought of as disease-causing when interrogating 20–30 genes for a child with ambiguous genitalia, while the probability is lower for a patient with intellectual disability, which is associated with more than 300 genes on our multiplexed test.

Interpretation of nucleotide variants is further complicated by the ubiquity of variants of unknown significance and the lack of a comprehensive clinical grade reference databases. In a verification study, Bell et al. reported that 122 out of 460 literature-annotated disease mutations are either erroneous or benign polymorphisms, as evidenced by a frequency of >5% in samples tested and/or homozygosity in unaffected individuals.[9] This highlights the need for cautious and informed interpretation, which in some cases will require functional studies, confirmatory testing and sequencing of family members.

Communication of Results to Physicians

The communication of NGS results to clinicians poses many challenges. Great care must also be taken to educate physicians, particularly about variants of unknown significance (VUS) in the face of enthusiasm for diagnosis and gene discovery. Previous guidelines, developed in the context of serial single-gene testing, called for reporting of all VUS, a practice that would overwhelm physicians and patients with data that may be anxiety provoking and susceptible to misinterpretation. In our institution, whole-exome sequencing from a single individual reveals 130,000–140,000 variants. Approximately 98% of these are category 4 variants (unlikely to be disease causing) for reasons such as high allele frequency.[10] When faced with a variant in a gene of interest, physicians unfamiliar with NGS and the ubiquity of nucleotide variation may be dubious that a variant is not likely to be disease causing. A challenge when drafting NGS result reports is to accurately characterize pertinent findings in a format that is meaningful to a variety of subspecialists.[11] An electronic report is in development, which will contain the key findings and interpretation. We envision ‘point-of-care’ educational resources such as hyperlinks to disease information and resources or brief education modules that physicians would have the opportunity to view when pertinent to the case at hand. As McGuire and Burke noted: “If genomic research is to achieve its promise, investments in health outcomes research, health technology assessment, clinical practice guidelines and information tools will need to increase”.[12]

Communication of Results to Patients & Families

For patients, post-test counseling with a geneticist or genetic counselor is important. In addition to diagnostic findings, an institution may determine that secondary findings will be conveyed to patients who have chosen to receive them following meaningful pretest counseling. As defined by ACMG, secondary findings are “gene variants known to be associated with a phenotype, but not believed to be related to the condition that led to the testing”.[102] In order to facilitate the discussion of results, some institutions have adopted a staged release of results where diagnostic results are included in a primary report, including incidental findings that have clear medical interventions. An optional full report including all variants may also be requested. Our current approach to pediatric patients is to report only variants predicted to be causative of the child’s symptoms. Confirmatory Sanger sequencing of research results is performed such that all results are clinically actionable.

In cutting-edge genomic medicine, novel variants and genes are routinely identified that may be associated with unknowns such as: pleiotropy (the effect of a single gene on multiple phenotypic traits), epistasis (gene–gene interactions), phenotypic heterogeneity, incomplete penetrance and epigenetic processes. An additional complication is that variant interpretation may change. Some of today’s VUS will become interpretable as genomic reference databases improve. There is a lack of consensus about whether there is a duty to recontact patients and families whose interpretation has changed, and if so, who is responsible for contacting families.[13] Furthermore, the practicalities of such reanalysis have scarcely been considered.

A vital member of our research team is a genetic counselor who is well versed in the complexities of molecular medicine and NGS, and will guide and support families. The need for highly specialized patient and family support is exemplified by the case of a family whose first-born child suffered a rapidly painful and life-threatening neonatal disease [Saunders CJ et al., Rapid whole genome sequencing for genetic disease diagnosis in neonatal intensive care units (2012), Manuscript in preparation]. Clinical testing was nondiagnostic and the parents consented to NGS for themselves and their child. Shortly after consent the patient passed away, and the family was faced with the decision of whether to seek a postmortem molecular diagnosis. Their decision-making process necessitated contemplation of complex scientific concepts, including that of de novo dominant mutations versus rare recessive disorders, and the implication of such findings for family planning. In a case as this one, a misinterpreted variant could have serious unintended consequences for future pregnancies.

A recognized psychosocial benefit of genetic testing in symptomatic children is reduction of uncertainty. For both treatable and untreatable conditions, patients and family members may derive benefit from identification of a definitive etiology or elimination of specific genetic diseases from the differential diagnosis. The power of NGS to change pediatric healthcare, and most importantly to affect the lives of children today was seen among the first patients enrolled at the Children’s Mercy Hospital Center for Pediatric Genomic Medicine [Soden SE et al., A systematic approach to implementing monogenic genomic medicine (2012), Manuscript in preparation]. We enrolled siblings with progressive neurologic symptoms who, despite a 5-year etiologic investigation costing more than US$20,000 had not been identified with a causal etiology. Using NGS, a diagnosis was made and confirmed in our clinical laboratory within 6 weeks. These findings brought a diagnostic odyssey to an end for the family and their healthcare team. At the time of diagnosis the younger sister was 5 years of age, the same age at which her older sister’s symptoms, particularly cerebellar atrophy and ataxia, accelerated. At the time of diagnosis the younger child had only very mild ataxia. However, her sister’s condition had progressed such that a wheelchair was needed for ambulation, speech was dysarthric and upper extremity dysmetria and chorea were prominent. Faced with uncertainty about both daughters’ prognoses, and a differential that included fatal neurodegenerative diseases, the quest for diagnosis had intensified. Following molecular diagnosis with NGS, the literature could be drawn upon and the family reasured that individuals with this genetic diagnosis commonly live into adulthood with intact cognitive abilities. Furthermore, reports of coenzyme Q10 deficienty in individuals with this diagnosis, who reponded to coenzyme Q10 administration, prompted cautious optimism that a treatment to potentially slow disease progression had been identified.


This early report from the frontlines of genomic medicine suggests some of the ways that genomic medicine might come to be used and some of the ethical issues that might arise. The technologies are changing rapidly. The uses to which those technologies can be put are also rapidly changing. The ethical issues that arise from new uses of new technologies cannot be satisfactorily analyzed until they are understood and they cannot be understood until the technologies are deployed in the real world. Uncertainty is inherent in these projects. One response to uncertainty is to assume the worst, become risk-averse, and put roadblocks in the way of innovation until innovation has been proven safe. But innovation cannot be proven safe in a risk averse environment. The only way to assess the risks of a new technology is to use it – cautiously, carefully, with an open mind and a willingness to collect data that will allow an assessment of the risks and benefits. We should strive, as hard as we can, to minimize risks to the early adopters, even if doing so means we slow progress, prohibit certain seemingly desirable and potentially beneficial activities, and restrict the range of human choice. But we should not become so risk-averse as to abjure progress because of fear of unlikely, unproven, and even unnamed risks.

Such an approach would allow experimentation even as we remain exquisitely attentive to the ethical issues that arise as we innovate, and respond to those issues in a tentative but cautious way. Many of the fears that swirled around the early use of genomic technology have not been realized. Instead, adults have shown themselves to be more capable of dealing with troubling information, potentially bad news and uncertainty than they were once thought to be.[103] They have also shown themselves capable of deciding for themselves what they do and do not want to know.[14]

Testing children, of course, raises different concerns – but not so different. As with adults, genetic testing can either provide a precise diagnosis or it can provide probabilistic information about the risks of developing particular diseases. Both sorts of information may be useful, even crucial, to parents. Current guidelines dictate that testing should not be done for conditions that do not have any health implications during childhood. Such rules are probably wise in most circumstances. In some situations, as we learn more about the natural history of genetic conditions, or as we develop interventions that might prevent the onset of such conditions, the conventional wisdom about testing children for such conditions might change.

It may be, then, that the proper question to ask is not whether genetic information should be treated like other medical information – but instead, why other medical information should not be treated like genetic information. That is, why is all medical information not the property of the patient, rather than the property of the doctor? Why do patients not have the right to see all of their test results, rather than having those results reported to their doctors?

Genetic information may transform other medical information in part because it is becoming available at a time and in a form that makes it similar to other information that is widely and publically available. Steven Pinker, who was one of the first people in the world to have his whole genome sequenced, wrote: “People who have grown up with the democratization of information will not tolerate paternalistic regulations that keep them from their own genomes”.[15]

We should continue to innovate, analyze the implications of innovation and allow the technology to shape the questions to which ethics offers responses.

Future Perspective

Inexpensive and accurate whole-genome sequencing will soon be available to all doctors and to all citizens. The availability of this technology will challenge prevailing ethical and regulatory paradigms not just in genetics but in all of medicine. Massive amounts of complex data will require doctors to learn more about genetics, information scientists to develop ways of making sense of the data and patients (including parents of patients) to make decisions about what they want to know, when they want to know it, and how they want to access the information. Today’s projects are the pilot projects in which we must carefully explore the risks and benefits of new approaches to testing and to talking about test results.


Executive Summary

  • Current regulation of genomics reflects past eugenic abuses.
  • New technologies, which allow rapid and inexpensive whole-exome or -genome sequencing, raise questions about whether restrictive regulation is either feasible or appropriate.
  • We describe a program that we are developing at Children’s Mercy Hospital in Kansas City (MO, USA) to use next-generation sequencing techniques to test symptomatic children for hundreds of known autosomal recessive conditions.
  • We have developed an approach to informed consent and to disclosure of results that tries to balance clinicians’ desires to make the correct diagnosis, parents’ rights to make medical decisions for their children, and the child’s right to an open future.


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