Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications

Abstract

Next-generation sequencing (NGS) is now more accessible to clinicians and researchers. As a result, our understanding of the genetics of neurodevelopmental disorders (NDDs) has rapidly advanced over the past few years. NGS has led to the discovery of new NDD genes with an excess of recurrent de novo mutations (DNMs) when compared to controls. Development of large-scale databases of normal and disease variation has given rise to metrics exploring the relative tolerance of individual genes to human mutation. Genetic etiology and diagnosis rates have improved, which have led to the discovery of new pathways and tissue types relevant to NDDs. In this review, we highlight several key findings based on the discovery of recurrent DNMs ranging from copy number variants to point mutations. We explore biases and patterns of DNM enrichment and the role of mosaicism and secondary mutations in variable expressivity. We discuss the benefit of whole-genome sequencing (WGS) over whole-exome sequencing (WES) to understand more complex, multifactorial cases of NDD and explain how this improved understanding aids diagnosis and management of these disorders. Comprehensive assessment of the DNM landscape across the genome using WGS and other technologies will lead to the development of novel functional and bioinformatics approaches to interpret DNMs and drive new insights into NDD biology.

De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability

“…Intellectual disability (ID) is a clinically heterogeneous cognitive disorder with an overall prevalence of approximately 1%–3% in the general population (Boyle et al., ; Iwase et al., ; Maulik, Mascarenhas, Mathers, Dua, & Saxena, ; Wilfert et al., ). The introduction of diagnostic whole exome sequencing (WES) has been particularly successful identifying autosomal dominant (AD) (de novo) causes for ID (de Ligt et al., ; Veltman & Brunner, ; Yang et al., ).…”

Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder

“…However, one potential systematic explanation is that BRSK2 is less deeply covered in exomes, and the observed enrichment, in part, reflects the effects of the genome sequencing that was used for the HudsonAlpha probands described here. It has been shown previously that genome sequencing provides better coverage, in general, over coding exons than exome sequencing does, 27,31,[33][34][35][36] and that some exons, including among clinically relevant genes, tend to be more poorly covered by exomes. 36 We find that BRSK2 is less well covered by exomes than by genomes in gnomAD (Figure 3).…”

De novo variants in population constrained fetal brain enhancers and intellectual disability

“…The identification of genes that are recurrently mutated across multiple disease individuals has been a major route to discover novel disease genes 69 . We identified recurrent variants within three fetal brain enhancer clusters associated with genes involved in nervous system development (CSMD1, OLFM1, POU3F3), and found that this enrichment was significant relative to expectations.…”