Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents

Abstract

Recurrent copy number variations (CNVs) are common causes of neurodevelopmental disorders (NDDs) and associated with a range of psychiatric traits. These CNVs occur at defined genomic regions that are particularly prone to recurrent deletions and duplications and often exhibit variable expressivity and incomplete penetrance. Robust estimates of the population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders (NDD CNVs) are lacking. Here we perform array-based CNV calling in 12,252 mother–father–child trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and analyse the inheritance pattern of 26 recurrent NDD CNVs in 13 genomic regions. We estimate the total prevalence of recurrent NDD CNVs (duplications and deletions) in live-born children to 0.48% (95% C.I.: 0.37–0.62%), i.e., ~1 in 200 newborns has either a deletion or duplication in these NDDs associated regions. Approximately a third of the newborn recurrent NDD CNVs (34%, N = 20/59) are de novo variants. We provide prevalence estimates and inheritance information for each of the 26 NDD CNVs and find higher prevalence than previously reported for 1q21.1 deletions (~1:2000), 15q11.2 duplications (~1:4000), 15q13.3 microdeletions (~1:2500), 16p11.2 proximal microdeletions (~1:2000) and 17q12 deletions (~1:4000) and lower than previously reported prevalence for the 22q11.2 deletion (~1:12,000). In conclusion, our analysis of an unselected and representative population of newborns and their parents provides a clearer picture of the rate of recurrent microdeletions/duplications implicated in neurodevelopmental delay. These results will provide an important resource for genetic diagnostics and counseling.

The Phenotypic Spectrum of 15q13.3 Region Duplications: Report of 5 Patients

“…Coe et al (2014) found no significant enrichment of small duplications involving CHRNA7 in a cohort of pediatric patients with various developmental disorders compared with controls [ 24 ]. Similarly, Smajlagić et al (2020) focused on population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders finding that duplications involving only CHRNA7 and/or OTUD7A genes are common, in comparison with deletions involving the same region [ 31 ]. The authors also suggested that these duplications are phenotypically neutral [ 31 ].…”

“…Similarly, Smajlagić et al (2020) focused on population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders finding that duplications involving only CHRNA7 and/or OTUD7A genes are common, in comparison with deletions involving the same region [ 31 ]. The authors also suggested that these duplications are phenotypically neutral [ 31 ].…”

A Tiered Genetic Screening Strategy for the Molecular Diagnosis of Intellectual Disability in Chinese Patients

“…Compared to the 2011 version ( Kearney et al, 2011 ), the point-based scoring metric for CNVs paid more attention to the genomic content, the inheritance pattern, and the correlations of clinical findings. With extensive application of NGS-based techniques in clinical laboratories, more abundant variation databases across different races would lead to more consistency across interpretations ( Smajlagić et al, 2021 ; Yuan et al, 2021 ).…”

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

“…Studies were admitted to this paper’s analysis when the following criteria were met: (1) the study detailed parent of origin data for one of the 38 eligible NAHR-mediated loci as designated by Coe et al [ 7 ], (2) the authors of the study interrogated the entire canonical CNV interval to confirm the presence of a deletion or duplication in the patients, (3) the authors determined the investigated CNVs were de novo, and (4) the study clearly treated monozygotic twins as one meiotic event and not two (Additional file 1 : Supplemental Methods, Additional file 2 : Table S1, and Additional file 3 : Table S2). The literature search led to a manual review of 1268 papers, out of which we identified 77 manuscripts across 24 loci with suitable data for analysis: 1q21.1 [ 35 – 39 ], 1q21.1 TAR [ 40 ], 2q13 [ 37 ], 3q29 [ 37 – 42 ], 5q35 [ 31 , 32 ], 7q11.23 [ 24 , 40 , 43 – 54 ], 8p23.1 [ 55 , 56 ], 11q13.2q13.4 [ 57 ], 15q13.3 [ 38 , 40 , 58 ], 15q24 (AC, AD, BD, and BE intervals) [ 59 – 64 ], 15q25.2 [ 65 – 67 ],16p11.2 [ 26 , 37 , 40 , 68 – 70 ], distal 16p11.2 [ 37 , 38 , 70 ], 16p11.2p12.1 [ 71 ], 16p31.11 [ 37 ], 17p11.2 [ 72 – 76 ], 17q11.2 [ 28 , 29 , 77 ], 17q12 [ 37 , 38 , 78 ], 17q21.31 [ 19 , 25 , 67 , 79 – 84 ], 17q23.1q23.2 [ 69 , 85 ] and 22q11.2 [ 30 , 43 …”

“…Data are consolidated by locus. BED coordinates correspond to hg38 (LiftOver from hg18 coordinates in Coe et al[7])intervals)[59][60][61][62][63][64], 15q25.2[65][66][67],16p11.2[26,37,40,[68][69][70], distal 16p11.2[37,38,70], 16p11.2p12.1[71], 16p31.11[37], 17p11.2[72][73][74][75][76], 17q11.2[28,29,77], 17q12[37,38,78], 17q21.31[19,25,67,[79][80][81][82][83][84], 17q23.1q23.2[69,85] and 22q11.2[30,43,53,[86][87][88][89]…”