A clear bias in parental origin of de novo pathogenic CNVs related to intellectual disability, developmental delay and multiple congenital anomalies

Abstract

Copy number variation (CNV) is of great significance in human evolution and disorders. Through tracing the parent-of-origin of de novo pathogenic CNVs, we are expected to investigate the relative contributions of germline genomic stability on reproductive health. In our study, short tandem repeat (STR) and single nucleotide polymorphism (SNP) were used to determine the parent-of-origin of 87 de novo pathogenic CNVs found in unrelated patients with intellectual disability (ID), developmental delay (DD) and multiple congenital anomalies (MCA). The results shown that there was a significant difference on the distribution of the parent-of-origin for different CNVs types (Chi-square test, p = 4.914 × 10−3). An apparently paternal bias existed in deletion CNVs and a maternal bias in duplication CNVs, indicating that the relative contribution of paternal germline variations is greater than that of maternal to the origin of deletions, and vice versa to the origin of duplications. By analyzing the sequences flanking the breakpoints, we also confirmed that non-allelic homologous recombination (NAHR) served as the major mechanism for the formation of recurrent CNVs whereas non-SDs-based mechanisms played a part in generating rare non-recurrent CNVs and might relate to the paternal germline bias in deletion CNVs.

Pronounced maternal parent-of-origin bias for type-1 NF1 microdeletions

“…As an alternative to replication-associated mechanisms, non-recurrent CNVs can be caused by various DNA double strand repair mechanisms that are not dependent upon sequence homology at the breakpoints, e,g, non-homologous end joining (NHEJ) (reviewed in Weckselblatt and Rudd, 2015). Previous studies have indicated that de novo non-recurrent CNVs, in particular deletions, are preferentially of paternal origin (Thomas et al 2006a;Itsara et al 2010;Hehir-Kwa et al 2011;Sibbons et al 2012;Ma et al 2017). This bias could be explicable in terms of the higher number of cell divisions (and hence replications) in the male as compared with the female germline.…”

“…Whilst the number of oogonia in females is fixed at birth and will not increase later in life, self-renewing spermatogenic stem cells undergo continuous proliferation and replication during a male's lifespan (reviewed by Drost and Lee, 1995;Wilson Sayres and Makova, 2011;Griswold, 2016). The higher number of cell divisions (and replications) in the male germ line is likely to be the cause of the paternal parent-of-origin bias for de novo mutations (Kong et al 2012;Rahbari et al 2016) and may also explain the paternal bias for large structural imbalances such as non-recurrent CNVs (Ma et al 2017).…”

De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families

“…The larger size of SVs increases the likelihood that any given SV will impact protein-coding genes or other critical genomic regions. Understanding the selective constraints on dnSV-specific mechanisms is essential because a broad spectrum of balanced, unbalanced, and complex structural mutations are known to underlie many developmental disorders (Ma et al 2017;Chiang et al 2012;Talkowski et al 2012;Xu et al 2008;Stefansson et al 2008). However, dnSVs are predicted to occur several hundred-fold less frequently than point mutations , requiring a much larger sample size to achieve accurate estimates of dnSV rates.…”

Sex-specific recombination predicts parent of origin for recurrent genomic disorders

“…To our knowledge, this study is the first comprehensive investigation of parental origin of NAHRmediated CNV loci. Hehir-Kwa et al, and Ma et al, conducted similar large-scale studies, focusing on intellectual disability, developmental delay and congenital dysmorphisms, and determined a paternal bias for a sample predominantly of non-recurrent CNV 77,78 . They hypothesized that replication-based mechanisms of CNV formation contributed to the bias.…”