TY - JOUR
T1 - Diagnostic Gene Panel Testing in (Non)-Syndromic Patients with Cleft Lip, Alveolus and/or Palate in the Netherlands
AU - Wurfbain, Lisca Florence
AU - Cox, Inge Lucia
AU - van Dooren, Maria Francisca
AU - Lachmeijer, Augusta Maria Antonia
AU - Verhoeven, Virginie Johanna Maria
AU - van Hagen, Johanna Maria
AU - Heijligers, Malou
AU - Wassink-Ruiter, Jolien Sietske Klein
AU - Koene, Saskia
AU - Maas, Saskia Mariska
AU - Veenstra-Knol, Hermine Elisabeth
AU - van Amstel, Johannes Kristian Ploos
AU - Massink, Maarten Pieter Gerrit
AU - van der Molen, Aebele Barber Mink
AU - van den Boogaard, Marie-Jose Henriette
PY - 2023/8/1
Y1 - 2023/8/1
N2 - 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.
AB - 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.
KW - Cleft lip
KW - Cleft alveolus
KW - Cleft palate
KW - Genetics
KW - Gene panel
KW - ORAL CLEFTS
KW - MORPHOLOGICAL ABNORMALITIES
KW - ASSOCIATION
KW - ANOMALIES
KW - VARIANTS
KW - IMPACT
U2 - 10.1159/000530256
DO - 10.1159/000530256
M3 - Article
SN - 1661-8769
VL - 14
SP - 270
EP - 282
JO - Molecular Syndromology
JF - Molecular Syndromology
IS - 4
ER -