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. 2023 Aug;14(4):270-282.
doi: 10.1159/000530256. Epub 2023 Jun 8.

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

Lisca Florence Wurfbain  1   2 , Inge Lucia Cox  1   2 , Maria Francisca van Dooren  3 , Augusta Maria Antonia Lachmeijer  2 , Virginie Johanna Maria Verhoeven  3 , Johanna Maria van Hagen  4 , Malou Heijligers  5 , Jolien Sietske Klein Wassink-Ruiter  6 , Saskia Koene  7 , Saskia Mariska Maas  4 , Hermine Elisabeth Veenstra-Knol  6 , Johannes Kristian Ploos van Amstel  2 , Maarten Pieter Gerrit Massink  2 , Aebele Barber Mink van der Molen  1 , Marie-José Henriette van den Boogaard  2
Affiliations

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

Lisca Florence Wurfbain et al. Mol Syndromol. 2023 Aug.

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.

Keywords: Cleft alveolus; Cleft lip; Cleft palate; Gene panel; Genetics.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

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