Scherer, Stephen W.

BackgroundCardiomyopathy is a clinically and genetically heterogeneous heart condition that can lead to heart failure and sudden cardiac death in childhood. While it has a strong genetic basis, the genetic aetiology for over 50% of cardiomyopathy cases remains unknown.MethodsIn this study, we analyse the characteristics of tandem repeats from genome sequence data of unrelated individuals diagnosed with cardiomyopathy from Canada and the United Kingdom (n = 1216) and compare them to those found in the general population. We perform burden analysis to identify genomic and epigenomic features that are impacted by rare tandem repeat expansions (TREs), and enrichment analysis to identify functional pathways that are involved in the TRE-associated genes in cardiomyopathy. We use Oxford Nanopore targeted long-read sequencing to validate repeat size and methylation status of one of the most …

The genetic correlates of extreme impulsive violence are poorly understood, and there have been few studies that have characterized a large group of affected individuals both clinically and genetically. We performed whole exome sequencing (WES) in 290 males with the life‐course‐persistent, extremely impulsively violent form of antisocial personality disorder (APD) and analyzed the spectrum of rare protein‐truncating variants (rPTVs). Comparisons were made with 314 male controls and publicly available genotype data. Functional annotation tools were used for biological interpretation. Participants were significantly more likely to harbor rPTVs in genes that are intolerant to loss‐of‐function variants (odds ratio [OR] 2.06; p < 0.001), specifically expressed in brain (OR 2.80; p = 0.036) and enriched for those involved in neurotransmitter transport and synaptic processes. In 60 individuals (20%), we identified …

SCN2A is an autism spectrum disorder (ASD) risk gene and encodes a voltage-gated sodium channel. However, the impact of ASD-associated SCN2A de novo variants on human neuron development is unknown. We studied SCN2A using isogenic SCN2A–/– induced pluripotent stem cells (iPSCs), and patient-derived iPSCs harboring a de novo R607* truncating variant. We used Neurogenin2 to generate excitatory (glutamatergic) neurons and found that SCN2A+/R607* and SCN2A–/– neurons displayed a reduction in synapse formation and excitatory synaptic activity. We found differential impact on actional potential dynamics and neuronal excitability that reveals a loss-of-function effect of the R607* variant. Our study reveals that a de novo truncating SCN2A variant impairs the development of human neuronal function.

Knowledge of genetic diversity and structure is essential for developing conservation strategies for endangered species. Blue whales were hunted to near extinction in the mid-twentieth century. Not-withstanding almost 380,000 animals killed globally, much remains unknown about their population structure and migration patterns. Herein, we use whole genome sequencing to elucidate the poorly understood population genetics of North Atlantic (NA) blue whales. We generated a de novo genome assembly for a NA blue whale to analyze 19 other whole genomic sequences and 31 complete mitochondrial genomes. Present-day and historical samples (earliest from 1876) from the Atlantic and Antarctic Oceans were included to understand the impact of whaling on the genetic diversity of this species. We found low but statistically significant population structuring and high genetic diversity. Demographic modeling …

The human PLAA gene encodes Phospholipase-A2-Activating-Protein (PLAA) involved in trafficking of membrane proteins. Through its PUL domain (PLAP, Ufd3p, and Lub1p), PLAA interacts with p97/VCP modulating synaptic vesicles recycling. Although few families carrying biallelic PLAA variants were reported with progressive neurodegeneration, consequences of monoallelic PLAA variants have not been elucidated. Using exome or genome sequencing we identified PLAA de-novo missense variants, affecting conserved residues within the PUL domain, in children affected with neurodevelopmental disorders (NDDs), including psychomotor regression, intellectual disability (ID) and autism spectrum disorders (ASDs). Computational and in-vitro studies of the identified variants revealed abnormal chain arrangements at C-terminal and reduced PLAA-p97/VCP interaction, respectively. These findings expand both allelic and phenotypic heterogeneity associated to PLAA-related neurological disorders, highlighting perturbed vesicle recycling as a potential disease mechanism in NDDs due to genetic defects of PLAA.

Autism spectrum disorder (ASD) encompasses a heterogeneous group of conditions diagnosed by clinicians solely on the basis of behavioral assessments that reveal social communication deficits and repetitive behaviors. Individuals with ASD are increasingly being seen in clinical genetics. More than 100 genetic disorders that can exhibit features of ASD and dozens of rare susceptibility genes and copy number variation (CNV) loci have been identified, which combined, depending on the study, can facilitate a molecular diagnosis in ~5%–40% of ASD cases. So far, none of the known CNVs or genes account for more than 1% of ASD cases, and often different pathogenic variants are found within the same family. The likelihood of a genetic finding in ASD increases with the complexity of the phenotype (e.g., idiopathic or related to a specific genetic disorder or syndrome, with or without intellectual disability) and the …

We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. Multiple classes of P/LP variants included single-nucleotide variants (SNVs)/indels (6.7%), copy number variations (3.4%) and mitochondrial mutations (1.5%). The COL4A1 gene had the most P/LP SNVs. We also analyzed two pediatric control cohorts (n = 203 trios and n = 89 sib-pair families) to provide a baseline for de novo mutation rates and genetic burden analyses, the latter of which demonstrated associations between de novo deleterious variants and genes related to the nervous system. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11A and CYP51A1). A …

BackgroundWe present genomic and phenotypic findings of a transgenerational family consisting of three male offspring, each with a maternally inherited distal 220 kb deletion at locus 16p11.2 (BP2–BP3). Genomic analysis of all family members was prompted by a diagnosis of autism spectrum disorder (ASD) in the eldest child, who also presented with a low body mass index.MethodsAll male offspring underwent extensive neuropsychiatric evaluation. Both parents were also assessed for social functioning and cognition. The family underwent whole-genome sequencing. Further data curation was undertaken from samples ascertained for neurodevelopmental disorders and congenital abnormalities.ResultsOn medical examination, both the second and third-born male offspring presented with obesity. The second-born male offspring met research diagnostic criteria for ASD at 8 years of age and presented with …