The contribution of X-linked coding variation to severe developmental disorders

Abstract

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.

Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome

“…Although the proportion of X-linked genes involved in neurodevelopmental disorders is recognized to be higher than autosomal genes, less is known about the specific effects of many rare X-linked variants in complex traits such as cognition. [41] The PLXNA3 predicted deleterious missense variants in our subjects are either novel or have a very low allele frequencies (less than 1/10,000) and thus the power of the loss-of-function observed/expected upper bound fraction (LOEUF) metric (currently estimated as 0.384 for PLXNA3) is limited. However, the probability of loss-of-function intolerance (pLI ≥ 0.9) metric for PLXNA3 predicts a high level of constraint.…”

The Usefulness of a Targeted Next Generation Sequencing Gene Panel in Providing Molecular Diagnosis to Patients With a Broad Spectrum of Neurodevelopmental Disorders

“…Several mechanisms might cause this bias, including sex hormones, as suggested for testosterone exposure in fetal life in ASD ( Baron-Cohen et al, 2015 ). Possible genetic mechanisms underlying this gender seem not to involve X-linked variants, since X-linked ID is too rare to account for the 30% excess of males with this disorder and a recent burden analysis on a large group of patients with NDDs reported that X-linked causal variants were carried in similar proportions of males (6%) and females (6.9%) ( Martin et al, 2021 ). Our panel allows good coverage of X-linked genes, since it includes 67 of the 130 X-linked genes that have been implicated in NNDs, and detected X-linked variants in two males and 10 females, with seven originated de novo .…”

Re-evaluation and Re-analysis of 152 research exomes five years after the initial report reveals clinically relevant changes in 20%

“…Due to insufficient information in population data banks and challenges in classifying inherited X-linked variants, most TAF1 variants have unknown significance. 24 This family shows how consanguinity can obscure alternative inheritance patterns. We couldn't classify this variant as pathogenic without segregation analysis, which emphasizes the need to store index, parent, and affected family DNA samples.…”