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...
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2021
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oai:doaj.org-article:44bd90137bd44131872e1f1eb901a15b2021-12-02T16:31:02ZClinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood10.1038/s41598-021-94958-z2045-2322https://doaj.org/article/44bd90137bd44131872e1f1eb901a15b2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94958-zhttps://doaj.org/toc/2045-2322Abstract 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.Ana Latorre-PellicerMarta Gil-SalvadorIlaria ParentiCristina Lucia-CamposLaura TrujillanoIñigo Marcos-AlcaldeMaría ArnedoÁngela AscasoAriadna Ayerza-CasasRebeca Antoñanzas-PérezCristina GervasiniMaria PiccioneMilena MarianiAxel WeberDeniz KanberAlma KuechlerMartin MunteanuKatharina KhullerGloria Bueno-LozanoBeatriz PuisacPaulino Gómez-PuertasAngelo SelicorniFrank J. KaiserFeliciano J. RamosJuan PiéNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021) |
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Medicine R Science Q Ana Latorre-Pellicer Marta Gil-Salvador Ilaria Parenti Cristina Lucia-Campos Laura Trujillano Iñigo Marcos-Alcalde María Arnedo Ángela Ascaso Ariadna Ayerza-Casas Rebeca Antoñanzas-Pérez Cristina Gervasini Maria Piccione Milena Mariani Axel Weber Deniz Kanber Alma Kuechler Martin Munteanu Katharina Khuller Gloria Bueno-Lozano Beatriz Puisac Paulino Gómez-Puertas Angelo Selicorni Frank J. Kaiser Feliciano J. Ramos Juan Pié Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood |
| description |
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. |
| format |
article |
| author |
Ana Latorre-Pellicer Marta Gil-Salvador Ilaria Parenti Cristina Lucia-Campos Laura Trujillano Iñigo Marcos-Alcalde María Arnedo Ángela Ascaso Ariadna Ayerza-Casas Rebeca Antoñanzas-Pérez Cristina Gervasini Maria Piccione Milena Mariani Axel Weber Deniz Kanber Alma Kuechler Martin Munteanu Katharina Khuller Gloria Bueno-Lozano Beatriz Puisac Paulino Gómez-Puertas Angelo Selicorni Frank J. Kaiser Feliciano J. Ramos Juan Pié |
| author_facet |
Ana Latorre-Pellicer Marta Gil-Salvador Ilaria Parenti Cristina Lucia-Campos Laura Trujillano Iñigo Marcos-Alcalde María Arnedo Ángela Ascaso Ariadna Ayerza-Casas Rebeca Antoñanzas-Pérez Cristina Gervasini Maria Piccione Milena Mariani Axel Weber Deniz Kanber Alma Kuechler Martin Munteanu Katharina Khuller Gloria Bueno-Lozano Beatriz Puisac Paulino Gómez-Puertas Angelo Selicorni Frank J. Kaiser Feliciano J. Ramos Juan Pié |
| author_sort |
Ana Latorre-Pellicer |
| title |
Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood |
| title_short |
Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood |
| title_full |
Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood |
| title_fullStr |
Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood |
| title_full_unstemmed |
Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood |
| title_sort |
clinical relevance of postzygotic mosaicism in cornelia de lange syndrome and purifying selection of nipbl variants in blood |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/44bd90137bd44131872e1f1eb901a15b |
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