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Unmasking familial CPX by WES and identification of novel clinical signs
Author(s) -
Demeer Bénédicte,
Revencu Nicole,
Helaers Raphael,
Devauchelle Bernard,
François Geneviève,
Bayet Bénédicte,
Vikkula Miikka
Publication year - 2018
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.40630
Subject(s) - exome sequencing , hypodontia , proband , genetics , medicine , choanal atresia , exome , candidate gene , phenotype , gene , biology , mutation , atresia , orthodontics , anatomy
Mutations in the T‐Box transcription factor gene TBX22 are found in X‐linked Cleft Palate with or without Ankyloglossia syndrome (CPX syndrome). In addition to X‐linked inheritance, ankyloglossia, present in the majority of CPX patients, is an important diagnostic marker, but it is frequently missed or unreported, as it is a “minor” feature. Other described anomalies include cleft lip, micro and/or hypodontia, and features of CHARGE syndrome. We conducted whole exome sequencing (WES) on 22 individuals from 17 “a priori” non‐syndromic cleft lip and/or cleft palate (CL/P) families. We filtered the data for heterozygous pathogenic variants within a set of predefined candidate genes. Two canonical splice‐site mutations were found in TBX22. Detailed re‐phenotyping of the two probands and their families unravelled orofacial features previously not associated with the CPX phenotypic spectrum: choanal atresia, Pierre‐Robin sequence, and overgrowths on the posterior edge of the hard palate, on each side of the palatal midline. This study emphasizes the importance of WES analysis in familial CLP cases, combined with deep (reverse) phenotyping in “a priori” non‐syndromic clefts.