De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

Abstract

Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent‐offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different—mostly constrained—genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio‐approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.

A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies

“…De novo variants were found in 32.5% of probands and represent 83.5% of all cases with a molecular diagnosis. These findings are consistent with previous studies of their contribution to NDD 1 , 5 , 26 , 27 . Both the paternal and maternal age (at proband birth) may impact the detection of de novo variants, as we observed a trend towards older paternal ( p = 0.076) and maternal ( p = 0.061) age in families with de novo variants, compared to all other families (with or without a molecular diagnosis).…”

“…Neurodevelopmental disorders (NDD), including global developmental delay (GDD) and intellectual disability (ID), constitute a wide and heterogeneous group of conditions affecting brain function, many of which are caused by a monogenic etiology 1 , 2 . While the diagnostic process for patients with NDD is often lengthy, the growing use of exome sequencing (ES) in the clinical setting has revolutionized the field of medical genetics 3 – 5 . Another group of patients who stand to benefit from ES are those with multiple congenital anomalies (MCA), especially when they remain undiagnosed following chromosomal microarray analysis (CMA) 6 – 8 .…”

Genetic Analysis of Children With Unexplained Developmental Delay and/or Intellectual Disability by Whole-Exome Sequencing

“…In this study, WES was performed for 17 probands with DD/ID with an overall diagnostic yield of 58.8% (10/17), which is consistent with a recent study that WES identified pathogenic variants in 53.5% (54/101) of patients with DD/ID ( Hiraide et al, 2021 ). A total of eight de novo variants were detected, including five SNVs/Indels and three CNVs, corroborating the burden of de novo variants in DD/ID ( Brunet et al, 2021 ). And further functional studies are needed to elucidate the effect of the identified variants at the transcriptional or translational level.…”

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

“…The genetic components of a large fraction of these psychiatric disorders are difficult to unravel since most of them are not necessarily Mendelian (dominant, recessive, or X-linked) and involve the participation of allelic variants in several genes ( Au et al, 2020 ; Savatt and Myers, 2021 ). However, it is estimated that approximately 40% of NDD are monogenic conditions predominantly due to lesions of a single gene ( Deciphering Developmental, and Disorders, 2017 ; Brunet et al, 2021 ), and this figure even rises to about 50% in the case of ID ( Kaufman et al, 2010 ; Karam et al, 2015 ; Reichenberg et al, 2016 ; Vissers et al, 2016 ). Because many of these vulnerable genes do not necessarily encode proteins specifically expressed in the brain with documented functions in neurodevelopment, our current understanding of disease pathogenesis remains extremely limited.…”