Parental mosaicism in de novo neurodevelopmental diseases

Abstract

Neurodevelopmental diseases are increasingly recognized to be caused by “de novo” variants with the expanding use of next‐generation sequencing. The apparent de novo variants may actually be low‐level hereditary parental mosaic variants, which could increase the recurrence risk of disease by >50% and is thought to be an underappreciated cause of neurodevelopmental diseases. Our study aimed to investigate the frequency of parental mosaicism in “de novo” neurodevelopmental diseases. A total of 237 patients (and parents) with neurodevelopmental diseases carrying apparent de novo pathogenic or likely pathogenic variants were recruited consecutively. Deep next‐generation sequencing was performed on parental samples to identify parental mosaicism. Fourteen parental disease‐causing mosaicism variants (3.0%) in 11 genes were detected with alternate allele frequency (AAF) 0.22%–34%. Three parents showed milder clinical phenotypes than their offspring with relatively high AAF (23.33%, 25%, 34% separately). One recurrent variant was identified prenatally. A review of cohort study on parental mosaicism in neurodevelopmental diseases was performed. Our study highlights that identifying the parental mosaic disease‐causing variants especially the low‐level mosaicism will contribute to improving the accuracy of genetic counseling and prenatal diagnosis for reproductive risks.

The contribution of mosaicism to genetic diseases and de novo pathogenic variants

“…Furthermore, we quantity the contribution of parental mosaicism to presumed de novo non‐mosaic disease (2.86% and 2.34% in the UDN and VEHR cohorts) in a non‐disease specific manner. Our findings fall in the range predicted in previous disease‐specific studies which estimated the disease‐specific prevalence of 0.5% and 8.3% (Acuna‐Hidalgo et al, 2015; Campbell, Yuan, et al, 2014; Domogala et al, 2021; Shu et al, 2021; Wright et al, 2019). We think this is likely to be an underestimation because low parental allele reads, or analysis pipelines prevent detection of low variant allele copy numbers and the lack of parental phenotypic exams conducted in routine practice.…”

“…PM variants could then be passed onto their children and presumed to be a de novo variant (Acuna‐Hidalgo et al, 2015). PM, therefore, may represent an underappreciated source of transmitted variants (Campbell, Yuan, et al, 2014; Shu et al, 2021).…”

Detection of low-level parental somatic mosaicism for clinically relevant SNVs and indels identified in a large exome sequencing dataset

“…Somatic mosaicism has been described in a wide variety of genetic disorders with all modes of inheritance and has been observed across different tissues [ 2 – 16 ]. Recent studies have shown that low-level somatic mosaic variants leading to neurodevelopmental disorders, congenital heart disease, and autism are more prevalent than previously thought [ 17 – 23 ].…”

Case report: A novel case of parental mosaicism in SMC1A gene causes inherited Cornelia de Lange syndrome

“…The same variant was found in another unrelated familial case, and despite it could never be confirmed in parents, its presence in both daughters was consistent with germline mosaicism ( Deardorff et al, 2007 ). Although non CdLS-related, an additional case of parental mosaicism in SMC1A was reported in a neurodevelopmental disease, but in this case the mother of the proband was not totally unaffected and suffered from epilepsy ( Shu et al, 2021 ).…”