A Genetic Study of 66 Individuals With Syndromic Velopharyngeal Insufficiency

ObjectiveVelopharyngeal insufficiency (VPI) is a form of velopharyngeal dysfunction caused by anatomical anomalies in the velopharyngeal sphincter. Although genetic causes such as 22q11 deletion syndrome are recognised, the broader genetic basis remains poorly understood. This study investigated the genetic aetiology of VPI.DesignWe conducted a phenotypic search on the DECIPHER database using the term 'Velopharyngeal Insufficiency' and identified genetic variants in these patients. These were classified using ACMG guidelines. Literature searches and network analyses examined gene roles and their contribution to sphincter development.PatientsWe identified 66 patients on DECIPHER with VPI.ResultsNinety-five percent of patients presented with syndromic VPI, commonly observed phenotypes included neurodevelopmental abnormalities and facial dysmorphology. Five patients (7.6%) had cleft palate. Pathogenic or likely pathogenic variants were identified in 56.1% of those with reported genetic variants (32/57); 26.3% through copy number variants and 29.8% through sequence variants (SVs). Chromosome 22q11.2 aberrations were the most frequently observed finding in the cohort; 7 patients carried deletions and 2 carried duplications. Independent truncating SVs in KMT2A and CAMTA1 were observed in multiple individuals. Network analyses and literature review of 26 genes prioritised for potential relevance to VPI revealed 2 broad functions: regulating gene expression and signalling pathways, contributing to palatogenesis and cranial-base development.ConclusionThis study demonstrates a high rate of pathogenic or likely pathogenic genetic findings in a syndromic VPI cohort. The findings highlight several recurrent genomic regions and biologically plausible genes that may contribute to VPI beyond the well-known 22q11 deletion syndrome.