Abstract
Rare copy number variations (CNVs) are a known genetic etiology in neurodevelopmental disorders (NDD). Comprehensive CNV analysis was performed in 287 Chinese children with mental retardation and/or development delay (MR/DD) and their unaffected parents. When compared with 5,866 ancestry-matched controls, 11~12% more MR/DD children carried rare and large CNVs. The increased CNV burden in MR/DD was predominantly due to de novo CNVs, the majority of which (62%) arose in the paternal germline. We observed a 2~3 fold increase of large CNV burden in the mothers of affected children. By implementing an evidence-based review approach, pathogenic structural variants were identified in 14.3% patients and 2.4% parents, respectively. Pathogenic CNVs in parents were all carried by mothers. The maternal transmission bias of deleterious CNVs was further replicated in a published dataset. Our study confirms the pathogenic role of rare CNVs in MR/DD, and provides additional evidence to evaluate the dosage sensitivity of some candidate genes. It also supports a population model of MR/DD that spontaneous mutations in males’ germline are major contributor to the de novo mutational burden in offspring, with higher penetrance in male than female; unaffected carriers of causative mutations, mostly females, then contribute to the inherited mutational burden.
Highlights
The second issue is interpretational: how to distinguish pathogenic from benign CNVs16,17? The inheritance status may not be used as a single criterion for evaluation: de novo occurrence may not necessarily imply pathogenicity[18]; and the role of inherited copy number variations (CNVs) should not be underestimated[19], but their interpretations are complicated by the incomplete penetrance and/or variable expressivity
CNVs identified in this clinical cohort were compared to 5,866 adult controls not ascertained for neurodevelopmental disorders (NDD)
We mainly focused on ultra-rare CNVs with population frequency
Summary
The second issue is interpretational: how to distinguish pathogenic from benign CNVs16,17? The inheritance status may not be used as a single criterion for evaluation: de novo occurrence may not necessarily imply pathogenicity[18]; and the role of inherited CNVs should not be underestimated[19], but their interpretations are complicated by the incomplete penetrance and/or variable expressivity. An evidence-based review approach has been recommended[20]. For this task, it is crucial to incorporate the findings from latest research. Studies in additional population can be valuable They allow an assessment of potential population difference in global CNV burden and locus-specific associations, which are still not fully clear. To shed light on the pathogenic roles of de novo and inherited CNVs, the CNV burdens in both children and their unaffected parents were compared against ~6,000 ancestry-matched controls. We compared the findings with previous reports in European populations; highlighted gender differences; and documented several cases of pathogenic and benign CNVs that may help refine the genome-wide dosage sensitivity map
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