Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders

Abstract

Background Structural rearrangements of the genome, which generally occur during meiosis and result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb), underlie genomic disorders. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR). Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs. However, the mechanism underlying these biases is not well understood. Methods We performed a systematic, comprehensive literature search to curate parent of origin data for multiple pathogenic CNV loci. Using a regression framework, we assessed the relationship between parental CNV origin and the male to female recombination rate ratio. Results We demonstrate significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci (p = 1.07 × 10–14). Conclusions Our results suggest that parental origin of CNVs is largely influenced by sex-specific recombination rates and highlight the need to consider these differences when investigating mechanisms that cause structural variation.

Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome

“…It also confers a >30fold increased risk for ASD, and exhibits pleiotropy for a range of phenotypes, including intellectual disability, developmental delay, attention deficit hyperactivity disorder (ADHD), and graphomotor deficits (38)(39)(40)(41). 3q29Del has a prevalence of approximately 1 in 30,000 and usually arises de novo during parental meiosis due to the hemizygous deletion of a 1.6-Mb locus, spanning 21 protein-coding genes (39,42). Although several genes within the interval have been proposed as putative drivers (43,44), it is not currently known which genes or biological mechanisms contribute to the emergence of abnormal neurodevelopmental phenotypes in 3q29Del.…”

Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome

“…The 3q29 deletion (3q29Del) is a relatively recently discovered CNV associated with an exceptionally increased burden of neurodevelopmental disability. 3q29Del has a prevalence of ~1 in 30,000 and usually arises de novo due to the hemizygous deletion of a 1.6-Mb locus, spanning 21 protein-coding genes [18,19]. Cognitive ability in individuals with 3q29Del is typically in the range of mild-to-moderate ID, with deficits of variable severity observed in both non-verbal and verbal reasoning, a complex profile characterized by relative strengths in verbal compared to non-verbal IQ, and significant correlations identified between cognitive disability and adaptive functioning [18,20].…”