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.

[1]  D. Liang,et al.  Partial trisomy 2q33.3-q37.3 in a patient with an inverted duplicated neocentric marker chromosome , 2015, Molecular Cytogenetics.

[2]  Timothy B. Stockwell,et al.  The Diploid Genome Sequence of an Individual Human , 2007, PLoS biology.

[3]  J. Crow,et al.  Population biology of genes and molecules , 1990 .

[4]  H. McDermid,et al.  Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms , 2003, Journal of medical genetics.

[5]  John Wei,et al.  Towards a comprehensive structural variation map of an individual human genome , 2010, Genome Biology.

[6]  K. Kuma,et al.  Male-driven Molecular Evolution demonstrated by Different Rates of Silent Substitutions between Autosome- and Sex Chromosome-linked Genes , 1987 .

[7]  N. Rahman,et al.  Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome , 2005, Journal of Medical Genetics.

[8]  R. Sandford,et al.  Parental and chromosomal origins of microdeletion and duplication syndromes involving 7q11.23, 15q11-q13 and 22q11 , 2006, European Journal of Human Genetics.

[9]  J. Drost,et al.  Biological basis of germline mutation: Comparisons of spontaneous germline mutation rates among drosophila, mouse, and human , 1995, Environmental and molecular mutagenesis.

[10]  J C Murray,et al.  Pediatrics and , 1998 .

[11]  Leslie G Biesecker,et al.  Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. , 2010, American journal of human genetics.

[12]  Yong-shu He,et al.  [Structural variation in the human genome]. , 2009, Yi chuan = Hereditas.

[13]  Gary D Bader,et al.  Functional impact of global rare copy number variation in autism spectrum disorders , 2010, Nature.

[14]  Bradley P. Coe,et al.  Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV. , 2016, American journal of human genetics.

[15]  S. Ferrari,et al.  Author contributions , 2021 .

[16]  A. Auton,et al.  Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes. , 2013, American journal of human genetics.

[17]  K. Johnson.  An Update. , 1984, Journal of food protection.

[18]  P. Marynen,et al.  Unequal meiotic crossover: a frequent cause of NF1 microdeletions. , 2000, American journal of human genetics.

[19]  J. Sebat,et al.  CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics , 2012, Cell.

[20]  Kenny Q. Ye,et al.  Large-Scale Copy Number Polymorphism in the Human Genome , 2004, Science.

[21]  K. Kuma,et al.  Male-driven molecular evolution: a model and nucleotide sequence analysis. , 1987, Cold Spring Harbor symposia on quantitative biology.

[22]  Deborah A Nickerson,et al.  De novo rates and selection of large copy number variation. , 2010, Genome research.

[23]  J. R. MacDonald,et al.  A copy number variation map of the human genome , 2015, Nature Reviews Genetics.

[24]  I. Schubert,et al.  Mechanisms of Chromosome Rearrangements , 2013 .

[25]  N. S. Thomas,et al.  Parental and chromosomal origin of unbalanced de novo structural chromosome abnormalities in man , 2006, Human Genetics.

[26]  P. Stankiewicz,et al.  Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. , 2009, Human molecular genetics.

[27]  P. Stankiewicz,et al.  Genome architecture, rearrangements and genomic disorders. , 2002, Trends in genetics : TIG.

[28]  D. Gudbjartsson,et al.  A high-resolution recombination map of the human genome , 2002, Nature Genetics.

[29]  J. Lupski,et al.  Mechanisms for human genomic rearrangements , 2008, PathoGenetics.

[30]  Z. Ou,et al.  Microdeletions including YWHAE in the Miller–Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment , 2009, Journal of Medical Genetics.

[31]  Yu Wang,et al.  A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures , 2008, Nature Genetics.

[32]  Rong Li,et al.  Genome Analyses of Single Human Oocytes , 2013, Cell.

[33]  S. South,et al.  American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants , 2011, Genetics in Medicine.

[34]  J. Lupski,et al.  A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders , 2007, Cell.

[35]  Tomas W. Fitzgerald,et al.  Origins and functional impact of copy number variation in the human genome , 2010, Nature.

[36]  Carl Baker,et al.  Evolution and diversity of copy number variation in the great ape lineage , 2013, Genome research.

[37]  L. Vallée,et al.  Telomeric 22q13 deletions resulting from rings, simple deletions, and translocations: cytogenetic, molecular, and clinical analyses of 32 new observations , 2003, Journal of medical genetics.

[38]  Y. Fukushima,et al.  Preferential paternal origin of microdeletions caused by prezygotic chromosome or chromatid rearrangements in Sotos syndrome. , 2003, American journal of human genetics.

[39]  Cécile Fizames,et al.  A comprehensive genetic map of the human genome based on 5,264 microsatellites , 1996, Nature.

[40]  Joshua M. Korn,et al.  Association between microdeletion and microduplication at 16p11.2 and autism. , 2008, The New England journal of medicine.

[41]  M. K. Rudd,et al.  Human Structural Variation: Mechanisms of Chromosome Rearrangements. , 2015, Trends in genetics : TIG.

[42]  D. Conrad,et al.  Global variation in copy number in the human genome , 2006, Nature.

[43]  L. Vissers,et al.  De novo copy number variants associated with intellectual disability have a paternal origin and age bias , 2011, Journal of Medical Genetics.

[44]  K. Gunderson,et al.  Increased LIS1 expression affects human and mouse brain development , 2009, Nature Genetics.

[45]  Andrew J Sharp,et al.  The genetics of microdeletion and microduplication syndromes: an update. , 2014, Annual review of genomics and human genetics.