6533b82bfe1ef96bd128d8e2
RESEARCH PRODUCT
Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood.
Iñigo Marcos-alcaldeIñigo Marcos-alcaldeAxel WeberCristina Lucia-camposAriadna Ayerza-casasJuan PiéFeliciano J. RamosGloria Bueno-lozanoKatharina KhullerMaría Teresa Echeverría ArnedoAngelo SelicorniIlaria ParentiLaura TrujillanoMarta Gil-salvadorMilena MarianiPaulino Gómez-puertasRebeca Antoñanzas-pérezAna Latorre-pellicerBeatriz PuisacÁNgela AscasoCristina GervasiniFrank J. KaiserMartin MunteanuMaria PiccioneAlma KuechlerDeniz Kanbersubject
AdultMaleCornelia de Lange SyndromeAdolescent Adult Cell Cycle Proteins Child Child Preschool Comparative Genomic Hybridization De Lange Syndrome Female Gene Deletion High-Throughput Nucleotide Sequencing Humans Male Middle Aged Mosaicism Mutation Missense Phenotype Retrospective Studies Spain Young AdultAdolescentSomatic cellScienceGenetic counselingMedizinMutation MissenseDiseasesCell Cycle ProteinsBiologyPaediatric researchGermlineArticle03 medical and health sciencesNegative selectionYoung AdultMedical researchDe Lange SyndromeGenetics researchmedicineMissense mutationHumansClinical significanceChild030304 developmental biologyRetrospective StudiesGenetics0303 health sciencesComparative Genomic HybridizationMultidisciplinaryMosaicismQ030305 genetics & heredityRHigh-Throughput Nucleotide SequencingNIPBLMiddle Agedmedicine.diseasePhenotypeSettore MED/03 - Genetica MedicaSpainChild PreschoolMedicineFemaleGene Deletiondescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-07-01 |