SDCCAG8 – Senior-Loken Syndrome

Senior-Loken syndrome is an autosomal recessive ciliopathy characterized by nephronophthisis and retinal degeneration. Biallelic variants in SDCCAG8 (NPHP10) have been implicated in patients presenting with early-onset renal failure and retinopathy, redefining SDCCAG8 as an SLS locus (PMID:22190896). In one report, two independent probands harboring compound heterozygous or homozygous truncating SDCCAG8 variants, including c.849_852del (p.Leu282_Cys283insTer), displayed nephronophthisis with concomitant retinal degeneration and absence of extrarenal features such as polydactyly (PMID:22190896).

Mechanistic studies demonstrate that the C-terminal region of SDCCAG8 is essential for centrosomal localization and cilia formation. A mouse model with targeted truncation of the SDCCAG8 C-terminus exhibits cystic kidney changes, retinal degeneration, and other ciliopathy phenotypes, supporting haploinsufficiency as a pathogenic mechanism (PMID:35131266). These data, while limited in human case numbers, are concordant with experimental evidence and suggest a contributory role for SDCCAG8 in Senior-Loken syndrome.

Key take-home: SDCCAG8 should be included in genetic testing panels for autosomal recessive nephronophthisis with retinal degeneration to guide early diagnosis and management.

References

• Molecular syndromology | 2011 | Mutations in SDCCAG8/NPHP10 Cause Bardet-Biedl Syndrome and Are Associated with Penetrant Renal Disease and Absent Polydactyly. PMID:22190896
• 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)