The CCDC32 gene is located on chromosome 15 at 15q15.1 and encodes coiled-coil domain-containing protein 32, which has a role in cephalic and left-right axis development, as well as cilia formation and maintenance. CCDC32 was first reported in relation to autosomal recessive cardiofacioneurodevelopmental syndrome (CFNDS) in 2020 (Harel et al., PMID: 32307552). CFNDS is characterized by cardiac defects, craniofacial features including bilateral cleft lip and palate, and developmental delays. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Three variants (including 2 frameshift variants and an intragenic deletion) that have been reported in three probands in two publications (PMIDs:32307552, 35451546) are included in this curation. An additional 21 kb deletion was reported in a fourth proband (PMID: 38818818) but was not included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence from zebrafish models (PMID: 32307552). Zebrafish with depleted ccdc32 display cerebellar hypoplasia, microcephaly, altered facial skeletal morphology, disrupted cardiac looping, and impaired expression of a ket left/right patterning transcript (southpaw).
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date October 18th, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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