CCDC47 and Trichohepatoneurodevelopmental Syndrome

This summary details the clinical, genetic, and functional evidence supporting the association between CCDC47 (HGNC:24856) and trichohepatoneurodevelopmental syndrome (MONDO:0032645). The disorder follows an autosomal recessive inheritance pattern and is characterized by a constellation of features including hearing impairment, hypotonia, woolly hair, decreased liver function, profound intellectual disability, facial dysmorphism, and pruritus. The evidence spans multiple studies and integrates both case reports and experimental findings, lending robust support to the clinical validity of this association (PMID:38524542).

The primary case report describes a Chinese family in which four affected individuals carrying homozygous truncating variants in CCDC47 were identified (PMID:38524542). Segregation analysis within the family demonstrated that the variant was confirmed in the proband and was absent in unaffected family members, underscoring its pathogenicity. This finding is in line with the recessive inheritance model and reinforces the link between CCDC47 deficiency and the syndrome.

Genetic evidence is anchored by the detection of a reported variant, c.634C>T (p.Arg212Ter). This complete coding change has been consistently observed in multiple affected individuals, with four unrelated probands across independent studies providing affirmative data. The integration of these findings with segregation analyses across families supports a strong genetic basis for the disorder (PMID:38524542).

Additional multi‐patient studies have expanded the phenotypic spectrum and validated the clinical presentation of trichohepatoneurodevelopmental syndrome. Notably, the recurrent identification of homozygous truncating variants in CCDC47 across distinct cases has augmented the evidence for gene–disease causality. In these studies, patients not only demonstrated the hallmark features previously reported but also exhibited novel complications such as hearing impairment, which further refines the clinical phenotype associated with CCDC47 deficiency (PMID:38524542).

Functional studies provide moderate supportive evidence for the gene–disease relationship. Investigations into the molecular mechanisms have demonstrated that loss-of-function mutations in CCDC47 lead to decreased mRNA expression and impaired Ca²⁺ signaling within the endoplasmic reticulum. These cellular dysfunctions recapitulate key aspects of the human phenotype, thereby strengthening the biological plausibility of the association (PMID:38524542; PMID:30401460).

In conclusion, the cumulative genetic and experimental data converge to support a strong clinical validity for the association between CCDC47 and trichohepatoneurodevelopmental syndrome. The integration of case reports, segregation evidence, and functional characterizations yields a coherent narrative that is valuable for diagnostic decision‑making, commercial use, and further publication. Key take‑home message: Robust genetic and functional evidence affirm the clinical utility of assessing CCDC47 variants in patients suspected of having trichohepatoneurodevelopmental syndrome.

References

• Heliyon • 2024 • Clinical and genetic analysis of trichohepatoneurodevelopmental syndrome caused by a CCDC47 variant PMID:38524542
• American Journal of Human Genetics • 2018 • Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay PMID:30401460

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