Gonadal mosaicism of large terminal de novo duplication and deletion in siblings with variable intellectual disability phenotypes

Abstract

BackgroundIntellectual disability (ID) is a complex condition that can impact multiple domains of development. The genetic contribution to ID’s etiology is significant, with more than 100 implicated genes and loci currently identified. The majority of such variants are rare and de novo genetic mutations.MethodsWe have applied whole‐genome microarray to identify large, rare, clinically relevant copy number variants (CNVs). We have applied well‐established algorithms for variants call. Quantitative polymerase chain reaction (qPCR) was applied to validate the variants using three technical replicates for each family member. To assess whether the copy number variation was due to balanced translocation or mosaicism, we further conducted droplet digital PCR (ddPCR) on the whole family. We have, as well, applied “critical‐exon” mapping, human developmental brain transcriptome, and a database of known associated neurodevelopmental disorder variants to identify candidate genes.ResultsHere we present two siblings who are both impacted by a large terminal duplication and a deletion. Whole‐genome microarray revealed an 18.82 megabase (MB) duplication at terminal locus (7q34‐q36.3) of chromosome 7 and a 3.90 MB deletion impacting the terminal locus (15q26.3) of chromosome 15. qPCR and ddPCR experiments confirmed the de novo origin of the variants and the co‐occurrence of these two de novo events among the siblings, but their absence in both parents, implicates an unbalanced translocation that could have mal‐segregated among the siblings or a possible germline mosaicism. These terminal events impact IGF1R, CNTNAP2, and DPP6, shown to be strongly associated with neurodevelopmental disorders. Detailed clinical examination of the siblings revealed the presence of both shared and distinct phenotypic features.ConclusionsThis study identified two large rare terminal de novo events impacting two siblings. Further phenotypic investigation highlights that even in the presence of identical large high penetrant variants, spectrum of clinical features can be different between the siblings.

Construction of copy number variation landscape and characterization of associated genes in a Bangladeshi cohort of neurodevelopmental disorders

“…Subtelomeric regions are gene-rich and particularly prone to genomic instability due to the repeat sequences found in these areas. Mutation in these regions causes a variety of phenotypic abnormalities, particularly intellectual disability (ID) ( Linardopoulou et al, 2005 ; Ruiter et al, 2007 ; Wu et al, 2010 ; Uddin et al, 2011 ; Rahman et al, 2019 ). Rahman et al (2019) identified two siblings affected with ID who are both impacted by large terminal duplication (18.82 Mb) and deletion (3.90 Mb) CNVs.…”

“…Therefore, early diagnosis of NDD cases in children may lead to better outcomes through expeditious educational planning and therapeutics ( Filipek et al, 1999 ). In Bangladesh, the genetic cause of breast cancer, intellectual disability, and rare diseases was uncovered by whole-genome sequencing, whole-exome sequencing, targeted sequencing, chromosomal microarray analysis, and quantitative PCR ( Uddin K. M. F. et al, 2018 ; Akter et al, 2019 ; Rahman et al, 2019 ; Uddin et al, 2019 ; Akter et al, 2021 ). However, there is no comprehensive genetic study carried out with a large NDD cohort.…”

A paradigmatic autistic phenotype associated with loss of PCDH11Y and NLGN4Y genes

“…The new techniques of genetic analysis, including chromosomal microarray and next-generation sequencing, have yield the identification of over 100 genes whose de novo postzygotic mutations, identified notably using the resequencing technologies, have significantly contributed to identifying the origins of many clinical features within the neurodevelopmental disorders [ 8 ]. A better understanding of the variants of uncertain significance (VUS), of the intronic variants, and of mosaic mutations will further contribute to the identifying of the genes responsible for the neurodevelopmental disorders [ 9 ].…”

Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh

“…Clinics in developing countries are not equipped with technologically advanced healthcare facilities for diagnosis and treatment. In Bangladesh, genetic tests are not widely used in a clinical setting and mostly applied for medical research purposes 4 , 5 . The current standard of care does not include first-tier genetic testing in most developing nations.…”