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This summary details the strong association between CCDC32 (HGNC:28295) and cardiofacioneurodevelopmental syndrome (MONDO:0030873). Multiple independent studies have reported homozygous loss-of-function variants in CCDC32 in unrelated individuals, establishing a consistent genotype–phenotype correlation (PMID:35451546). The reported cases include a novel patient as well as previously described individuals, thereby expanding the known clinical spectrum of the syndrome.
The core clinical features observed include bilateral conductive hearing impairment, short stature, hypoplasia of the corpus callosum, abnormal finger morphology, and intellectual disability. These symptoms collectively underscore a multi-system involvement that aligns with the characteristics of cardiofacioneurodevelopmental syndrome. Detailed phenotypic profiling across independent studies supports the clinical relevance of the association.
Genetic evidence is robust, with homozygous variants—such as the selected variant c.162_163dup (p.Glu55fs)—reported in three affected individuals (PMID:35451546). The autosomal recessive inheritance pattern is clearly demonstrated in these cases, and the loss-of-function mechanism is consistently observed across different variant classes. This variant, along with others in the gene, confirms that disruptions in CCDC32 are causally linked to the syndrome.
Segregation analyses in the reported families, although not extensive with additional affected relatives, reinforce the autosomal recessive inheritance pattern. The available data, derived from independent families, support the notion that the homozygous variants segregate with the disease phenotype. This reinforces the genetic causation and underscores the utility of molecular testing in suspected cases.
Functional studies provide moderate additional support for the gene–disease relationship. Experimental assessments using zebrafish models and mammalian cell cultures have demonstrated that ccdc32 depletion leads to defects in cilia formation and impaired clathrin-mediated endocytosis (PMID:32307552; PMID:38979322). These findings align well with the clinical observations and suggest that loss of CCDC32 function drives the pathogenic mechanism underlying cardiofacioneurodevelopmental syndrome.
In conclusion, the integration of multiple case reports, segregation data, and functional evidence supports a strong association between CCDC32 variants and cardiofacioneurodevelopmental syndrome. The consistent replication of these findings across independent studies enhances diagnostic confidence and fosters the development of precision diagnostic tools. Key take‑home: Molecular testing for CCDC32 mutations is clinically valuable and can substantially inform patient care for individuals exhibiting the hallmark features of this syndrome.
Gene–Disease AssociationStrongMultiple independent cases (3 probands [PMID:35451546]) demonstrating homozygous loss-of-function variants with supportive functional studies and consistent clinical phenotypes. Genetic EvidenceStrongHomozygous variants, including c.162_163dup (p.Glu55fs), reported in three unrelated individuals confirm a consistent autosomal recessive pattern with a coherent variant spectrum (PMID:35451546). Functional EvidenceModerateFunctional assays in zebrafish and cell models have demonstrated impaired cilia formation and disrupted clathrin-mediated endocytosis, supporting the pathogenic mechanism (PMID:32307552; PMID:38979322). |