Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population.

Multiple malformation syndromes (MMS) belong to a group of genetic disorders characterised by neurodevelopmental anomalies and congenital malformations. Here we explore for the first time the genetic aetiology of MMS using whole-exome sequencing (WES) in undiagnosed patients from the Greek-Cypriot p...

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Autores principales:	Evie Kritioti, Athina Theodosiou, Thibaud Parpaite, Angelos Alexandrou, Nayia Nicolaou, Ioannis Papaevripidou, Nina Séjourné, Bertrand Coste, Violetta Christophidou-Anastasiadou, George A Tanteles, Carolina Sismani
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c361d68fa02b47d5abaf3fa68d1c32fc
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spelling	oai:doaj.org-article:c361d68fa02b47d5abaf3fa68d1c32fc2021-12-02T20:09:00ZUnravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population.1932-620310.1371/journal.pone.0253562https://doaj.org/article/c361d68fa02b47d5abaf3fa68d1c32fc2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0253562https://doaj.org/toc/1932-6203Multiple malformation syndromes (MMS) belong to a group of genetic disorders characterised by neurodevelopmental anomalies and congenital malformations. Here we explore for the first time the genetic aetiology of MMS using whole-exome sequencing (WES) in undiagnosed patients from the Greek-Cypriot population after prior extensive diagnostics workup including karyotype and array-CGH. A total of 100 individuals (37 affected), from 32 families were recruited and family-based WES was applied to detect causative single-nucleotide variants (SNVs) and indels. A genetic diagnosis was reported for 16 MMS patients (43.2%), with 10/17 (58.8%) of the findings being novel. All autosomal dominant findings occurred de novo. Functional studies were also performed to elucidate the molecular mechanism relevant to the abnormal phenotypes, in cases where the clinical significance of the findings was unclear. The 17 variants identified in our cohort were located in 14 genes (PCNT, UBE3A, KAT6A, SPR, POMGNT1, PIEZO2, PXDN, KDM6A, PHIP, HECW2, TFAP2A, CNOT3, AGTPBP1 and GAMT). This study has highlighted the efficacy of WES through the high detection rate (43.2%) achieved for a challenging category of undiagnosed patients with MMS compared to other conventional diagnostic testing methods (10-20% for array-CGH and ~3% for G-banding karyotype analysis). As a result, family-based WES could potentially be considered as a first-tier cost effective diagnostic test for patients with MMS that facilitates better patient management, prognosis and offer accurate recurrence risks to the families.Evie KritiotiAthina TheodosiouThibaud ParpaiteAngelos AlexandrouNayia NicolaouIoannis PapaevripidouNina SéjournéBertrand CosteVioletta Christophidou-AnastasiadouGeorge A TantelesCarolina SismaniPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0253562 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Evie Kritioti Athina Theodosiou Thibaud Parpaite Angelos Alexandrou Nayia Nicolaou Ioannis Papaevripidou Nina Séjourné Bertrand Coste Violetta Christophidou-Anastasiadou George A Tanteles Carolina Sismani Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population.
description	Multiple malformation syndromes (MMS) belong to a group of genetic disorders characterised by neurodevelopmental anomalies and congenital malformations. Here we explore for the first time the genetic aetiology of MMS using whole-exome sequencing (WES) in undiagnosed patients from the Greek-Cypriot population after prior extensive diagnostics workup including karyotype and array-CGH. A total of 100 individuals (37 affected), from 32 families were recruited and family-based WES was applied to detect causative single-nucleotide variants (SNVs) and indels. A genetic diagnosis was reported for 16 MMS patients (43.2%), with 10/17 (58.8%) of the findings being novel. All autosomal dominant findings occurred de novo. Functional studies were also performed to elucidate the molecular mechanism relevant to the abnormal phenotypes, in cases where the clinical significance of the findings was unclear. The 17 variants identified in our cohort were located in 14 genes (PCNT, UBE3A, KAT6A, SPR, POMGNT1, PIEZO2, PXDN, KDM6A, PHIP, HECW2, TFAP2A, CNOT3, AGTPBP1 and GAMT). This study has highlighted the efficacy of WES through the high detection rate (43.2%) achieved for a challenging category of undiagnosed patients with MMS compared to other conventional diagnostic testing methods (10-20% for array-CGH and ~3% for G-banding karyotype analysis). As a result, family-based WES could potentially be considered as a first-tier cost effective diagnostic test for patients with MMS that facilitates better patient management, prognosis and offer accurate recurrence risks to the families.
format	article
author	Evie Kritioti Athina Theodosiou Thibaud Parpaite Angelos Alexandrou Nayia Nicolaou Ioannis Papaevripidou Nina Séjourné Bertrand Coste Violetta Christophidou-Anastasiadou George A Tanteles Carolina Sismani
author_facet	Evie Kritioti Athina Theodosiou Thibaud Parpaite Angelos Alexandrou Nayia Nicolaou Ioannis Papaevripidou Nina Séjourné Bertrand Coste Violetta Christophidou-Anastasiadou George A Tanteles Carolina Sismani
author_sort	Evie Kritioti
title	Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population.
title_short	Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population.
title_full	Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population.
title_fullStr	Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population.
title_full_unstemmed	Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population.
title_sort	unravelling the genetic causes of multiple malformation syndromes: a whole exome sequencing study of the cypriot population.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/c361d68fa02b47d5abaf3fa68d1c32fc
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Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population.

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