Wurfbain Lisca Florence, Cox Inge Lucia, van Dooren Maria Francisca, Lachmeijer Augusta Maria Antonia, Verhoeven Virginie Johanna Maria, van Hagen Johanna Maria, Heijligers Malou, Klein Wassink-Ruiter Jolien Sietske, Koene Saskia, Maas Saskia Mariska, Veenstra-Knol Hermine Elisabeth, Ploos van Amstel Johannes Kristian, Massink Maarten Pieter Gerrit, Mink van der Molen Aebele Barber, van den Boogaard Marie-José Henriette
Department of Pediatric Plastic Surgery, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Mol Syndromol. 2023 Aug;14(4):270-282. doi: 10.1159/000530256. Epub 2023 Jun 8.
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.
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.
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).
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.
唇、牙槽突和/或腭裂（CLA/P）是人类最常见的颅面先天性畸形。这些口腔裂隙可分为非综合征性（孤立性）和综合征性形式。许多与腭裂相关的综合征在临床上具有变异性且基因异质性，这使得区分综合征性和非综合征性病例具有挑战性。识别综合征性/遗传病因对于个性化定制护理、识别（未被认识到的）合并症以及准确的遗传咨询很重要。因此，基于下一代测序（NGS）的靶向基因panel检测在CLA/P患者的诊断中越来越多地被采用。在这项回顾性研究中，我们评估了NGS基因panel检测在一组CLA/P病例中的诊断率。
在2015年至2020年期间，对212例无关的CLA/P患者进行遗传咨询后，进行全外显子测序（WES），随后在先验选择的一组与CLA/P表型相关的基因中进行变异检测和解读。评估包括家族史和其他基因检测结果在内的病历。
在24例CLA/P病例（11.3%）中，鉴定出致病性基因变异。这24例中的20例患有需要特定监测和随访的遗传综合征。这24例中的6例（25%）在检测前被认为是孤立性CLA/P病例，占总队列的2.8%。在基于NGS的基因panel检测后未确诊的8例CLA/P病例（3.8%）中，通过额外的基因分析（如SNP阵列、单基因检测、三联体WES）建立了分子诊断。
本研究表明，基于NGS的基因panel检测是CLA/P患者诊断检查中的一种强大诊断工具。此外，在明显孤立的病例和非家族性病例中，也可以进行基因诊断。早期诊断有助于为患者提供个性化护理，并为其家庭提供准确的遗传咨询。
