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

Ruiyu Ma,Lingqian Wu,Rui Zhang,Jing Guo,Xianda Wei,Ruolan Guo,Linbei Deng,Yingxi Cao,Desheng Liang,Yan Xia

doi:10.1038/srep44446

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.

Highlights

Genome assembly, whereas SNPs encompassed only 0.1%
Ages of the probands span from 6 days to 34 years old. 65 patients carried CNVs overlapping with known chromosome syndromes like Wolf-Hirschhorn syndrome (WHS), Williams Beuren syndrome (WBS) and Angelman/Prader Willi syndrome (AS/PWS)
For some familiar recurrent genomic disorders, Thomas NS, et al.[16] determined the parental and chromosomal origins of several groups of patients involving 7q11.23, 15q11-q13 and 22q11, and no significant parental bias was observed except for duplications of 15q11-q13, which represented a maternal bias. They found a slight overall excess of maternal bias for 22q11 deletions when combining their data with those from previous studies. This bias was replicated and confirmed by Delio et al.[17] which a total of 810 combined results revealed a highly significant maternal bias occurring in the origin of the de novo 22q11.2 deletion

Summary

Introduction

Genome assembly, whereas SNPs encompassed only 0.1%. All these underscored one significant source of genetic variations in germ cell genome—CNVs. Nowadays, it is widely shared that CNVs derived from a variety of ways during the formation of germ cells, such as DNA repair, replication errors, homologous recombination and chromosome separation errors. The generation mechanism underlying these pathogenic CNVs has been studied extensively. Through tracing the origins and genesis mechanisms of these CNVs and exploring the relative contributions of the genome stability of sperms and eggs to reproductive health, we hope to know more about genome structure variations in germ cells, enhance the effective differential diagnosis and prenatal diagnosis of genomic disorders and to provide the potential for the prevention and treatment of related diseases in the future

Methods

Results

Conclusion