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Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders.

ABSTRACT: 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.

SUBMITTER: Costain G

PROVIDER: S-EPMC6366120 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders.

Costain Gregory G Walker Susan S Argiropoulos Bob B Baribeau Danielle A DA Bassett Anne S AS Boot Erik E Devriendt Koen K Kellam Barbara B Marshall Christian R CR Prasad Aparna A Serrano Moises A MA Stavropoulos D James DJ Twede Hope H Vermeesch Joris R JR Vorstman Jacob A S JAS Scherer Stephen W SW

Journal of neurodevelopmental disorders 20190207 1

<h4>Background</h4>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.<h4>Methods</h4>We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive o ...[more]

PMID: 30732576

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Project description:Chromosomal microarray (CMA) is now recommended as first tier for the evaluation in individuals with unexplained neurodevelopmental disorders (ND). However, in developing countries such as Brazil, classical cytogenetic tests are still the most used in clinical practice, as reflected by the scarcity of publications of microarray investigation in larger cohorts. This is a retrospective study which analyses the reading files of CMA and available clinical data from 420 patients from the south of Brazil, mostly children, with neurodevelopmental disorders requested by medical geneticists and neurologists for diagnostic purpose. Previous karyotyping was reported for 138 and includes 17 with abnormal results. The platforms used for CMA were CYTOSCAN 750K (75%) and CYTOSCAN HD (25%). The sex ratio of the patients was 1.625 males :1 female and the mean age was 9.5 years. A total of 96 pathogenic copy number variations (CNVs), 58 deletions and 38 duplications, were found in 18% of the patients and in all chromosomes, except chromosome 11. For 12% of the patients only variants of uncertain clinical significance were found. No clinically relevant CNV was found in 70%. The main referrals for chromosomal microarrays (CMA) were developmental delay (DD), intellectual disability (ID), facial dysmorphism and autism spectrum disorder (ASD). DD/ID were present in 80%, facial dysmorphism in 52% and ASD in 32%. Some phenotypes in this population could be predictive of a higher probability to carry a pathogenic CNV, as follows: dysmorphic facial features (p-value?=?<?0.0001, OR?=?0.32), obesity (p-value?=?0.006, OR?=?0.20), short stature (p-value?=?0.032, OR?=?0.44), genitourinary anomalies (p-value?=?0.032, OR?=?0.63) and ASD (p-value?=?0.039, OR?=?1.94). The diagnostic rate for CMA in this study was 18%. We present the largest report of CMA data in a cohort with ND in Brazil. We characterize the rare CNVs found together with the main phenotypes presented by each patient, list phenotypes which could predict a higher diagnostic probability by CMA in patients with a neurodevelopmental disorder and show how CMA and classical karyotyping results are complementary.

Dataset Information

Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders.

Publications

Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders.

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