Le Caignec, C. | bioRxiv Science

bioRxiv2018

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

PurposeTo assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations.\n\nMethodsWe analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations.\n\nResultsThe number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes.\n\nConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

genomics↗

bioRxiv2017

A framework to identify modifier genes in patients with Phelan-McDermid syndrome

Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability, speech impairment, and autism spectrum disorders (ASD). It results from a deletion of the 22q13 locus that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors modulating the severity of the syndrome remain largely unknown. In this study, we investigated 85 PMS patients with different 22q13 rearrangements (78 deletions, 7 duplications). We first explored their clinical features and provide evidence for frequent corpus callosum abnormalities. We then mapped candidate genomic regions at the 22q13 locus associated with risk of clinical features, and suggest a second locus associated with absence of speech. Finally, in some cases, we identified additional rearrangements at loci associated with ASD, potentially modulating the severity of the syndrome. We also report the first SHANK3 deletion transmitted to five affected daughters by a mother without intellectual disability nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.

genetics↗