An increased burden of rare exonic variants in NRXN1 microdeletion carriers is likely to enhance the penetrance for autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is characterized by a complex polygenic background, but with the unique feature of a subset of cases (~15%‐30%) presenting a rare large‐effect variant. However, clinical interpretation in these cases is often complicated by incomplete penetrance, variable expressivity and different neurodevelopmental trajectories. NRXN1 intragenic deletions represent the prototype of such ASD‐associated susceptibility variants. From chromosomal microarrays analysis of 104 ASD individuals, we identified an inherited NRXN1 deletion in a trio family. We carried out whole‐exome sequencing and deep sequencing of mitochondrial DNA (mtDNA) in this family, to evaluate the burden of rare variants which may contribute to the phenotypic outcome in NRXN1 deletion carriers. We identified an increased burden of exonic rare variants in the ASD child compared to the unaffected NRXN1 deletion‐transmitting mother, which remains significant if we restrict the analysis to potentially deleterious rare variants only (P = 6.07 × 10−5). We also detected significant interaction enrichment among genes with damaging variants in the proband, suggesting that additional rare variants in interacting genes collectively contribute to cross the liability threshold for ASD. Finally, the proband's mtDNA presented five low‐level heteroplasmic mtDNA variants that were absent in the mother, and two maternally inherited variants with increased heteroplasmic load. This study underlines the importance of a comprehensive assessment of the genomic background in carriers of large‐effect variants, as penetrance modulation by additional interacting rare variants to might represent a widespread mechanism in neurodevelopmental disorders.

Dissecting the multifaceted contribution of the mitochondrial genome to autism spectrum disorder

“…Recently, the largest exome sequencing study identified more than 100 high confidence ASD susceptibility genes implicated in brain development and synaptic transmission (Satterstrom et al, 2020). The genetic background of rare exonic variants in ASD susceptibility genes can also modulate the penetrance of large-effect variants, as we recently demonstrated for NRXN1 microdeletion carriers (Cameli et al, 2021). In addition, the burden of non-coding mutations has been demonstrated to contribute to the cumulative risk for ASD (Zhou et al, 2019).…”

Genetic modifiers of rare variants in monogenic developmental disorder loci

“…The related common variant burden has been shown to affect the phenotype in carriers of such variants 5 , 26 , suggesting that the cumulative effect of common variants can modify the penetrance of rare variants in such phenotypes, even when the primary cause is considered monogenic. While the impact of common variants on overall phenotypic expressivity has been examined for several neuropsychiatric 25 , 27 , 28 and other disease cohorts 29 – 31 , the modification of rare variant penetrance by other rare genetic variants has not been widely investigated because of the large cohort sizes required. Here, we present an analysis of common and rare variant burden in 419,854 adults from the UK Biobank (UKB) 32 .…”

Implications of the Neurexin Gene Family in Autism Spectrum Disorder

“…Researchers recorded an increased number of exonic rare variants in the ASD child compared to the unaffected mother. 8 One other recent study involved investigating the cognitive and behavioral skills of five children with a heterozygous NRXN1 deletion and four transmitting parents. Three of the five children were diagnosed with ASD and comorbidities, while the other two were diagnosed with an isolated intellectual disability and an unclassified neurodevelopmental disorder respectively.…”

“…10 The female proband with the inherited intragenic NRXN1 3p deletion exhibited a phenotype compatible with features of similar 3p deletion carriers such as dysthymic disorder (DD) and macrocephaly. 8 Epilepsy and seizures were also affiliated with heterozygous NRXN1 deletions, and three of the five children were diagnosed with intellectual disability or global developmental delay along with a major impairment in social communication skills in comorbidity with ASD. 9 NRXN2 19 rare and 1 common NRXN2 variants have been associated with ASD; the gene itself is located on chromosome 11q13.1.…”