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.
Highlights
Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications
Around 60–70% of affected individuals harbor a heterozygous loss-of-function pathogenic variant in the cohesin loading factor NIPBL, and approximately 5–10% of the cases have been associated with seven additional genes related to the cohesin complex (SMC1A, SMC3, RAD21, HDAC8, BRD4, ANKRD11 and MAU2)[15,16,17,18,19,20]
We report a total of 11 new cases of postzygotic mosaicism in individuals with CdLS from Germany, Italy and Spain
Summary
Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. 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. Mosaic mutations can go unnoticed, contribute to human variation, promote cancer, be involved in aging or underlie genetic diseases. In this context, several reviews have been published discussing the implication of mosaicism in human health and disease[4,5,6,7,8]. In contrast to what is commonly seen in other conditions, individuals with mosaic variants present with clinical features that are as severe as those observed in individuals harbouring constitutive pathogenic variants, and the two groups are clinically indistinguishable[13,25]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
