SDCCAG8 – Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by retinal dystrophy, obesity, cognitive impairment, hypogonadism and early-onset renal failure. SDCCAG8 (NPHP10/BBS16) encodes a centrosomal protein essential for cilia formation and organ homeostasis. Initial linkage of SDCCAG8 to nephronophthisis and retinopathy prompted investigation in multisystemic BBS cohorts, establishing SDCCAG8 as the sixteenth BBS locus (PMID:22190896).

Genetic evidence derives from 11 probands across 7 independent pedigrees with biallelic SDCCAG8 loss-of-function variants, including homozygous truncating mutations and compound heterozygous frameshift/splice defects, segregating in affected sibships (PMID:22190896; PMID:22626039). A recurrent frameshift, c.849_852del (p.Leu282_Cys283insTer), is observed in multiple families (PMID:22190896). No polydactyly was reported in these patients, while renal failure was fully penetrant.

Phenotypic spectrum of SDCCAG8-related BBS includes rod-cone dystrophy (HP:0000510), obesity (HP:0001513), cognitive impairment (HP:0100543), hypogonadism (HP:0000135) and infantile end-stage kidney disease. Global developmental delay and opsoclonus have been noted in isolated infantile nephronophthisis cases without classic BBS features (PMID:31534065).

Functional studies demonstrate that the C-terminal domain of SDCCAG8 is required for centrosomal localization and ciliogenesis in cultured cells, and Sdccag8-ΔC mice exhibit ciliopathy-like phenotypes including polydactyly, retinal degeneration and cystic kidney disease, mirroring human BBS16 pathology (PMID:35131266).

No studies to date have refuted the SDCCAG8–BBS association. Ciliopathy overlap with nephronophthisis and Senior-Loken syndrome underscores a shared pathogenic mechanism driven by defective primary cilia.

Together, autosomal recessive LoF variants in SDCCAG8 cause a distinct BBS subtype marked by absent polydactyly and fully penetrant renal failure. This strong gene-disease validity supports early genetic testing of SDCCAG8 in patients with BBS features and guides prognosis and management.

Key Take-home: Biallelic truncating or splice variants in SDCCAG8 define BBS16, characterized by early kidney failure, retinal dystrophy and obesity without polydactyly.

References

• Molecular syndromology • 2011 • Mutations in SDCCAG8/NPHP10 Cause Bardet-Biedl Syndrome and Are Associated with Penetrant Renal Disease and Absent Polydactyly. PMID:22190896
• Ophthalmic genetics • 2012 • Mutational analysis of SDCCAG8 in Bardet-Biedl syndrome patients with renal involvement and absent polydactyly. PMID:22626039
• The Tohoku journal of experimental medicine • 2019 • Rapidly Progressive Nephronophthisis in a 2-Year-Old Boy with a Homozygous SDCCAG8 Mutation. PMID:31534065
• The Journal of biological chemistry • 2022 • The carboxyl-terminal region of SDCCAG8 comprises a functional module essential for cilia formation as well as organ development and homeostasis. PMID:35131266

Evidence Based Scoring (AI generated)