Diagnostic Gene Panel Testing in (Non)-Syndromic Patients with Cleft Lip, Alveolus and/or Palate in the Netherlands

Lisca Florence Wurfbain, Inge Lucia Cox, Maria Francisca Van Dooren, Augusta Maria Antonia Lachmeijer, Virginie Johanna Maria Verhoeven, Johanna Maria Van Hagen, Malou Heijligers, Jolien Sietske Klein Wassink - Ruiter, Saskia Koene, Saskia Mariska Maas, Hermine Elisabeth Veenstra - Knol, Johannes Kristian Ploos Van Amstel, Maarten Pieter Gerrit Massink, Aebele Barber Mink Van Der Molen, Marie José Henriette Van Den Boogaard*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
48 Downloads (Pure)

Abstract

Objectives: Clefts of the lip, alveolus and/or palate (CLA/P) are the most common craniofacial congenital malformations in humans. These oral clefts can be divided into non-syndromic (isolated) and syndromic forms. Many cleft-related syndromes are clinically variable and genetically heterogeneous, making it challenging to distinguish syndromic from non-syndromic cases. Recognition of syndromic/genetic causes is important for personalized tailored care, identification of (unrecognized) comorbidities, and accurate genetic counseling. Therefore, next generation sequencing (NGS)-based targeted gene panel testing is increasingly implemented in diagnostics of CLA/P patients. In this retrospective study, we assess the yield of NGS gene panel testing in a cohort of CLA/P cases. Methods: Whole exome sequencing (WES) followed by variant detection and interpretation in an a priori selected set of genes associated with CLA/P phenotypes was performed in 212 unrelated CLA/P patients after genetic counseling between 2015 and 2020. Medical records including family history and results of additional genetic tests were evaluated. Results: In 24 CLA/P cases (11.3%), a pathogenic genetic variant was identified. Twenty out of these 24 had a genetic syndrome requiring specific monitoring and follow-up. Six of these 24 cases (25%) were presumed to be isolated CLA/P cases prior to testing, corresponding to 2.8% of the total cohort. In eight CLA/P cases (3.8%) without a diagnosis after NGS-based gene panel testing, a molecular diagnosis was established by additional genetic analyses (e.g., SNP array, single gene testing, trio WES). Conclusion: This study illustrates NGS-based gene panel testing is a powerful diagnostic tool in the diagnostic workup of CLA/P patients. Also, in apparently isolated cases and non-familial cases, a genetic diagnosis can be identified. Early diagnosis facilitates personalized care for patients and accurate genetic counseling of their families.

Original languageEnglish
Pages (from-to)270-282
Number of pages13
JournalMolecular Syndromology
Volume14
Issue number4
DOIs
Publication statusPublished - 1 Aug 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s). Published by S. Karger AG, Basel.

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