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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.
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BACKGROUND: Oral clefts-comprising cleft lip (CL), cleft lip with cleft palate (CLP), and cleft palate (CP)-are being diagnosed prenatally more frequently. Consequently, the need for accurate information on the risk of associated anomalies and chromosomal defects to aid in prenatal counselling is rising. This systematic review was conducted to investigate the prenatal and postnatal prevalence of associated anomalies and chromosomal defects related to cleft category, thereby providing a basis for prenatal counselling and prenatal invasive diagnostics. METHODS: Online databases were searched for prenatal and postnatal studies on associated anomalies and chromosomal defects in clefts. Data from the literature were complemented with national validated data from the Dutch Oral Cleft Registry. RESULTS: Twenty studies were included: three providing prenatal data, 13 providing postnatal data, and four providing both. Data from prenatal and postnatal studies showed that the prevalence of associated anomalies was lowest in CL (0-20.0% and 7.6-41.4%, respectively). For CLP, higher frequencies were found both prenatally (39.1-66.0%) and postnatally (21.1-61.2%). Although CP was barely detectable by ultrasound, it was the category most frequently associated with accompanying defects in postnatal studies (22.2-78.3%). Chromosomal abnormalities were most frequently seen in association with additional anomalies. In the absence of associated anomalies, chromosomal defects were found prenatally in CLP (3.9%) and postnatally in CL (1.8%, 22q11.2 deletions only), CLP (1.0%) and CP (1.6%). CONCLUSIONS: Prenatal counselling regarding prognosis and risk of chromosomal defects should be tailored to cleft category, and more importantly to the presence/absence of associated anomalies. Irrespective of cleft category, clinicians should advise invasive genetic testing if associated anomalies are seen prenatally. In the absence of associated anomalies, prenatal conventional karyotyping is not recommended in CL, although array comparative genomic hybridisation should be considered. In presumed isolated CLP or CP, prenatal invasive testing, preferably by array based methods, is recommended.