4.7 Article

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

Journal

SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41598-021-94958-z

Keywords

-

Funding

  1. Spanish Ministry of Health-ISCIII Fondo de Investigacion Sanitaria (FIS) [PI19/01860]
  2. Diputacion General de Aragon-FEDER: European Social Fund [B32_17R, B32_20R]
  3. Juan de la Cierva-Incorporacion postdoctoral grant from MICIU (Spanish Ministry of Science and Universities)
  4. Diputacion General de Aragon
  5. MH-ISCIII

Ask authors/readers for more resources

The high prevalence of mosaicism in CdLS patients, along with the negative selection against somatic deleterious NIPBL variants in blood, suggests a novel direction for clinical management and genetic counseling of families. The severity of symptoms in individuals with somatic mosaicism is comparable to those with constitutive pathogenic variants. Missense substitutions in NIPBL, even in the presence of mosaicism, are preferentially located within the HEAT repeat domain.
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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available