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In children undergoing genetic testing for physical health concerns, we examined how often the results also revealed information about their risk for neurodevelopmental disorders. The study sample consisted of 3056 genetic tests (1686 chromosomal microarrays--CMAs, and 1378 next-generation sequencing--NGS panels) ordered at a tertiary pediatric hospital because of a physical/congenital health problem. Tests ordered to investigate developmental concerns were excluded. Pathogenic, or likely pathogenic variants were manually reviewed for diagnostic likelihood, and for evidence of an association with a neurodevelopmental disorder (e.g., autism or intellectual disability). A total of 169 CMAs (10%) and 232 NGS panels (17%) had likely diagnostic results. More than half (52%) of all diagnostic results had established evidence of a neurodevelopmental disorder association. In summary, there is a high prevalence of neurodevelopmental implications from genetic tests ordered for physical/congenital indications. This broad clinical utility suggests a growing need for genetics-first developmental care pathways.

BACKGROUND: Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs. METHODS: We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases. RESULTS: We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs. CONCLUSIONS: Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data. ispartof: JOURNAL OF NEURODEVELOPMENTAL DISORDERS vol:11 issue:1 ispartof: location:England status: published

Key Points Question What is the diagnostic yield of genome sequencing in children with unexplained medical complexity and prior negative results of genetic testing? Findings In this cohort study that included 138 individuals from 49 families, genome sequencing detected all genomic variation previously identified by conventional genetic testing and resulted in a new diagnosis for 31% of patients. Meaning This study suggests that, because of its high yield, comprehensive nature, and increasingly competitive costs, genome sequencing is a potentially first-tier genetic test for children with unexplained medical complexity., Importance Children with medical complexity (CMC) represent a growing population in the pediatric health care system, with high resource use and associated health care costs. A genetic diagnosis can inform prognosis, anticipatory care, management, and reproductive planning. Conventional genetic testing strategies for CMC are often costly, time consuming, and ultimately unsuccessful. Objective To evaluate the analytical and clinical validity of genome sequencing as a comprehensive diagnostic genetic test for CMC. Design, Setting, and Participants In this cohort study of the prospective use of genome sequencing and comparison with standard-of-care genetic testing, CMC were recruited from May 1, 2017, to November 30, 2018, from a structured complex care program based at a tertiary care pediatric hospital in Toronto, Canada. Recruited CMC had at least 1 chronic condition, technology dependence (child is dependent at least part of each day on mechanical ventilators, and/or child requires prolonged intravenous administration of nutritional substances or drugs, and/or child is expected to have prolonged dependence on other device-based support), multiple subspecialist involvement, and substantial health care use. Review of the care plans for 545 CMC identified 143 suspected of having an undiagnosed genetic condition. Fifty-four families met inclusion criteria and were interested in participating, and 49 completed the study. Probands, similarly affected siblings, and biological parents were eligible for genome sequencing. Exposures Genome sequencing was performed using blood-derived DNA from probands and family members using established methods and a bioinformatics pipeline for clinical genome annotation. Main Outcomes and Measures The primary study outcome was the diagnostic yield of genome sequencing (proportion of CMC for whom the test result yielded a new diagnosis). Results Genome sequencing was performed for 138 individuals from 49 families of CMC (29 male and 20 female probands; mean [SD] age, 7.0 [4.5] years). Genome sequencing detected all genomic variation previously identified by conventional genetic testing. A total of 15 probands (30.6%; 95% CI 19.5%-44.6%) received a new primary molecular genetic diagnosis after genome sequencing. Three individuals had novel diseases and an additional 9 had either ultrarare genetic conditions or rare genetic conditions with atypical features. At least 11 families received diagnostic information that had clinical management implications beyond genetic and reproductive counseling. Conclusions and Relevance This study suggests that genome sequencing has high analytical and clinical validity and can result in new diagnoses in CMC even in the setting of extensive prior investigations. This clinical population may be enriched for ultrarare and novel genetic disorders. Genome sequencing is a potentially first-tier genetic test for CMC., This cohort study evaluates the analytical and clinical validity of genome sequencing as a comprehensive diagnostic genetic test for children with medical complexity.

The clinical use of whole-genome sequencing (WGS) is expected to alter pediatric medical management. The study aimed to describe the type and cost of healthcare activities following pediatric WGS compared to chromosome microarray (CMA). Healthcare activities prompted by WGS and CMA were ascertained for 101 children with developmental delay over 1 year. Activities following receipt of non-diagnostic CMA were compared to WGS diagnostic and non-diagnostic results. Activities were costed in 2016 Canadian dollars (CDN). Ongoing care accounted for 88.6% of post-test activities. The mean number of lab tests was greater following CMA than WGS (0.55 vs. 0.09; p = 0.007). The mean number of specialist visits was greater following WGS than CMA (0.41 vs. 0; p = 0.016). WGS results (diagnostic vs. non-diagnostic) modified the effect of test type on mean number of activities (p

Item does not contain fulltext Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.

Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability.