Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood

Abstract

Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of the affected individuals with mosaicism have a clinical phenotype at least as severe as those with constitutive pathogenic variants. However, the type of genetic change does not vary between germline and somatic events and, even in the presence of mosaicism, missense substitutions are located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the clinical management and genetic counselling of families.

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

“…The very low allele frequency found in the mother could explain the absence of clinical manifestations. However, this might not be so obvious in CdLS, considering that mosaic patients usually present clinical features as severe as those with constitutive pathogenic variants ( Latorre-Pellicer et al, 2021 ). Additionally, the arduousness in interpreting clinical presentation for SMC1A variant carrier females has been largely recognised ( Liu et al, 2009 ; Gervasini et al, 2013 ), as well as the gender differences observed in CdLS clinical expressivity when SMC1A is the affected gene.…”

“…The reason could fairly lie either in the lack of sensitiveness of the detection method or in the presence of the variant strictly in some germinal cells. However, the high prevalence of somatic mosaicism recently identified in CdLS patients, together with the disparity observed in tissue distribution of the pathogenic variant ( Latorre-Pellicer et al, 2021 ), suggests that we could be overlooking some cases of gonadosomatic mosaicism in parents, which, in case of detection, could have great impact on genetic counseling of affected families.…”

A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome

“…The patient´s DNA was analyzed on a panel of gene amplicons specifically designed for CdLS in the Clinical Genetics and Functional Genomics Group at the University of Zaragoza, as previously described [ 9 ]. The variants were classified according to the ACMG recommendations and detailed information provided in the public databases gnomAD ( (accessed on 7 March 2022)), ClinVar ( (accessed on 7 March 2022)), dbSNP ( (accessed on 7 March 2022)), LOVD ( (accessed on 7 March 2022)), and relevant scientific literature.…”

“…Currently, the widespread use of sequencing targeted panels, including causative and related CdLS genes, has significantly improved the diagnosis success rate, as well as reducing the time to achieve it [ 8 ]. However, although the causal variant of a CdLS case involves only one of the related genes, genetic diagnosis may still be challenging due to difficulties in interpretation such as allele frequency or even mosaicism, which appear to be quite recurrent in CdLS [ 9 ]. Furthermore, the genetic variant type can range from single-nucleotide variants (SNVs) to small insertions and deletions (INDELs) or copy number variants (CNVs).…”

Transcription Pause and Escape in Neurodevelopmental Disorders

“…Compensatory expression from the intact NIPBL allele is frequently observed and a reduction of ∼15% in expression is enough to observe a clinical phenotype ( Deardorff et al, 1993 ). Furthermore, somatic mosaicism for NIPBL mutations is reported in 10–23% of ‘classic CdLS’ diagnosed patients ( Huisman et al, 2013 ; Braunholz et al, 2015 ; Latorre-Pellicer et al, 2021 ).…”