Strong Association of De Novo Copy Number Mutations with Autism

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized

Rare copy number variation in cerebral palsy

As per publisher: published online 22 May 2013Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.Gai McMichael, Santhosh Girirajan, Andres Moreno-De-Luca, Jozef Gecz, Chloe Shard, Lam Son Nguyen, Jillian Nicholl, Catherine Gibson, Eric Haan, Evan Eichler, Christa Lese Martin and Alastair MacLenna

Correction to: ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

Correction to "ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

The American College of Medical Genetics and Genomics (ACMG) previously published guidance for reporting secondary findings in the context of clinical exome and genome sequencing (ES/GS) in 2013 and 2017. These recommendations were developed by the ACMG Secondary Findings Maintenance Working Group (SFWG), which was convened by the ACMG Board of Directors (BOD) to evaluate the need for a minimum list of genes that should be evaluated in individuals undergoing clinical ES/GS based on the medical actionability of the associated condition. In the past, policy recommendations concerning what types of variants to return along with lists of which genes to analyze were included. Given the increase in uptake of clinical ES/GS, the ACMG SFWG and BOD have agreed the list of recommended genes should now be updated annually. Policy updates surrounding the purpose, scope, and process for maintaining the ACMG Secondary Findings List are being published separately, and will be updated separately, as needed. It is important to reiterate here that use of the SF results should not be a replacement for indication-based diagnostic clinical genetic testing

Genes To Mental Health (G2MH): A framework to map the combined effects of rare and common variants on dimensions of cognition and psychopathology

Rare genomic disorders (RGDs) confer elevated risk for neurodevelopmental psychiatric disorders. In this era of intense genomics discoveries, the landscape of RGDs is rapidly evolving. However, there has not been comparable progress to date in scalable, harmonized phenotyping methods. As a result, beyond associations with categorical diagnoses, the effects on dimensional traits remain unclear for many RGDs. The nature and specificity of RGD effects on cognitive and behavioral traits is an area of intense investigation: RGDs are frequently associated with more than one psychiatric condition, and those studied to date affect, to varying degrees, a broad range of developmental and cognitive functions. Although many RGDs have large effects, phenotypic expression is typically influenced by additional genomic and environmental factors. There is emerging evidence that using polygenic risk scores in individuals with RGDs offers opportunities to refine prediction, thus allowing for the identification of those at greatest risk of psychiatric illness. However, translation into the clinic is hindered by roadblocks, which include limited genetic testing in clinical psychiatry, and the lack of guidelines for following individuals with RGDs, who are at high risk of developing psychiatric symptoms. The Genes to Mental Health Network (G2MH) is a newly funded National Institute of Mental Health initiative that will collect, share, and analyze large-scale data sets combining genomics and dimensional measures of psychopathology spanning diverse populations and geography. The authors present here the most recent understanding of the effects of RGDs on dimensional behavioral traits and risk for psychiatric conditions and discuss strategies that will be pursued within the G2MH network, as well as how expected results can be translated into clinical practice to improve patient outcomes

The Integration of Clinical Trials With the Practice of Medicine

Importance: Optimal health care delivery, both now and in the future, requires a continuous loop of knowledge generation, dissemination, and uptake on how best to provide care, not just determining what interventions work but also how best to ensure they are provided to those who need them. The randomized clinical trial (RCT) is the most rigorous instrument to determine what works in health care. However, major issues with both the clinical trials enterprise and the lack of integration of clinical trials with health care delivery compromise medicine's ability to best serve society. Observations: In most resource-rich countries, the clinical trials and health care delivery enterprises function as separate entities, with siloed goals, infrastructure, and incentives. Consequently, RCTs are often poorly relevant and responsive to the needs of patients and those responsible for care delivery. At the same time, health care delivery systems are often disengaged from clinical trials and fail to rapidly incorporate knowledge generated from RCTs into practice. Though longstanding, these issues are more pressing given the lessons learned from the COVID-19 pandemic, heightened awareness of the disproportionate impact of poor access to optimal care on vulnerable populations, and the unprecedented opportunity for improvement offered by the digital revolution in health care. Four major areas must be improved. First, especially in the US, greater clarity is required to ensure appropriate regulation and oversight of implementation science, quality improvement, embedded clinical trials, and learning health systems. Second, greater adoption is required of study designs that improve statistical and logistical efficiency and lower the burden on participants and clinicians, allowing trials to be smarter, safer, and faster. Third, RCTs could be considerably more responsive and efficient if they were better integrated with electronic health records. However, this advance first requires greater adoption of standards and processes designed to ensure health data are adequately reliable and accurate and capable of being transferred responsibly and efficiently across platforms and organizations. Fourth, tackling the problems described above requires alignment of stakeholders in the clinical trials and health care delivery enterprises through financial and nonfinancial incentives, which could be enabled by new legislation. Solutions exist for each of these problems, and there are examples of success for each, but there is a failure to implement at adequate scale. Conclusions and Relevance: The gulf between current care and that which could be delivered has arguably never been wider. A key contributor is that the 2 limbs of knowledge generation and implementation-the clinical trials and health care delivery enterprises-operate as a house divided. Better integration of these 2 worlds is key to accelerated improvement in health care delivery

5q14.3 neurocutaneous syndrome: a novel continguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C.

Haploinsufficiency of RASA1, located on chromosome 5q14.3, has been identified as the etiology underlying the disorder capillary malformation-arteriovenous malformation (CM-AVM). Recently, haploinsufficiency of MEF2C, located 1.33 Mb distal to RASA1 on chromosome 5q14.3, has been implicated as the genetic etiology underlying a complex array of deficits including mental retardation, hypotonia, absent speech, seizures, and brain anomalies. Here we report a patient who is haploinsufficient in both RASA1 and MEF2C who presents with dermatologic and neurologic abnormalities that constitute a 5q14.3 neurocutaneous syndrome. This finding highlights the need to assess for CM-AVM in patients with neurologic features consistent with MEF2C haploinsufficiency, and vice versa