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CCDC115-CDG is an autosomal recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in CCDC115. Initial exome sequencing in a family with three affected siblings identified a homozygous missense variant, c.92T>C (p.Leu31Ser), segregating with abnormal Golgi glycosylation and a storage-like phenotype (PMID:26833332).
Subsequent studies expanded the genetic spectrum to at least 12 affected individuals from six unrelated families, including three additional homozygous p.Leu31Ser cases, one compound heterozygote with a deletion allele, and two siblings homozygous for c.31G>T (p.Asp11Tyr) (PMID:26833332; PMID:29759592). Variants reported include missense, frameshift, and small indel alleles, with c.92T>C (p.Leu31Ser) being recurrent.
Clinically, patients present with early liver fibrosis progressing to cirrhosis, hypercholesterolemia, elevated alkaline phosphatase, copper metabolism defects, hepatosplenomegaly, and variable neurological involvement (PMID:29759592). The hepatic phenotype can mimic mitochondriopathies, Niemann-Pick C, or Wilson disease, leading to diagnostic delay.
Functional assays demonstrated abnormal N- and O-glycosylation on serum proteins and reduced sialic acid labeling in patient fibroblasts, which was fully restored by wild-type CCDC115 complementation. Localization studies placed CCDC115 in the ER-Golgi intermediate compartment and COPI vesicles, supporting a role in Golgi pH homeostasis and vesicular trafficking (PMID:26833332).
No studies to date dispute this association. The combined genetic and experimental data establish a strong gene–disease relationship under the ClinGen framework. CCDC115-CDG should be considered in patients with unexplained severe liver disease and glycosylation abnormalities.
Key Take-home: Screening for biallelic CCDC115 variants is critical for diagnosing CDG in patients with unexplained liver fibrosis, cirrhosis, and glycosylation defects.
Gene–Disease AssociationStrong12 probands from ≥6 unrelated families; consistent autosomal recessive segregation; concordant phenotype–genotype correlation Genetic EvidenceStrongMultiple missense and frameshift alleles in 12 affected individuals across 6 families with recessive segregation including recurrent c.92T>C (p.Leu31Ser) Functional EvidenceModerateCellular complementation restored glycosylation; localization and homology studies support Golgi trafficking mechanism |