A clear bias in parental origin of de novo pathogenic CNVs related to intellectual disability, developmental delay and multiple congenital anomalies.
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.
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, P.R. China.
Ruiyu
R
Ma
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, P.R. China.
Linbei
L
Deng
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, P.R. China.
Yan
Y
Xia
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, P.R. China.
Xianda
X
Wei
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, P.R. China.
Yingxi
Y
Cao
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, P.R. China.
Ruolan
R
Guo
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, P.R. China.
Rui
R
Zhang
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, P.R. China.
Jing
J
Guo
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, P.R. China.
Desheng
D
Liang
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, P.R. China.
Lingqian
L
Wu
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D015982:Bias; D002648:Child; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D018095:Germ-Line Mutation; D059765:Homologous Recombination; D006801:Humans; D040582:Inheritance Patterns; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D018895:Microsatellite Repeats; D020641:Polymorphism, Single Nucleotide