Mutations in SDCCAG8/NPHP10 Cause Bardet-Biedl Syndrome and Are Associated with Penetrant Renal Disease and Absent Polydactyly

Abstract

The ciliopathies are an expanding group of disorders caused by mutations in genes implicated in the biogenesis and function of primary cilia. Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by progressive retinal degeneration, obesity, polydactyly, cognitive impairment, kidney anomalies and hypogonadism. Mutations in SDCCAG8(NPHP10) were described recently in patients with nephronophthisis and retinal degeneration (Senior-Loken syndrome; SLS). Given the phenotypic and genetic overlap between known ciliopathy genes, we hypothesized that mutations in SDCCAG8 might also contribute alleles to more severe, multisystemic ciliopathies. We performed genetic and phenotypic analyses of 2 independent BBS cohorts. Subsequent to mutation screening, we made a detailed phenotypic analysis of 5 families mutated for SDCCAG8 (3 homozygous and 2 compound heterozygous mutations) and conducted statistical analyses across both cohorts to examine possible phenotype-genotype correlations with mutations at this locus. All patients with mutations in SDCCAG8 fulfilled the diagnostic criteria for BBS (retinal degeneration, obesity, cognitive defects, renal failure, hypogonadism). Interestingly, none of the patients with primary SDCCAG8 mutations had polydactyly, a frequent but not obligatory BBS feature. In contrast, the same patients displayed early-onset renal failure, obesity, as well as recurrent pulmonary and ENT infections. Comparison of the phenotypes of these families with our entire BBS cohort indicated that renal impairment and absent polydactyly correlated significantly with causal SDCCAG8 mutations. Thus, SDCCAG8 mutations are sufficient to cause BBS in 1-2% of our combined cohorts, and define this gene as the sixteenth BBS locus (BBS16). The absence of polydactyly and the concomitant, apparently fully penetrant association with early kidney failure represents the first significant genotype-phenotype correlation in BBS that potentially represents an indicator for phenotype-driven priority screening and informs specific patient management.

Fig. 1

Representation of families reported with mutations in SDCCAG8 (H.D.: Helene Dollfus; N.K.: Nicholas Katsanis).

Fig. 2

Mutations reported in SDCCAG8 to date. Mutations described in BBS patients are represented above the gene and mutations identified in SLS patients below. ESE = Exonic splicing enhancer.

Fig. 3

A, B Photographs of patients I.2.22 (A) and I.2.25 (B) showing the obesity (photograph from head to toe), normal extremities and retinitis pigmentosa (lower fundus photographs), respectively. C Photographs of patients II.22.21 (C1) and II.22.22 (C2) showing obesity with genu valgum orthopedic complications. D Photographs of patient II.30 showing excess of weight and normal extremities.

Fig. 4

Photographs showing different types of extremities found in Bardet-Biedl syndrome. A Normal extremities for an SDCCAG8 mutated patient. B Typical brachydactyly found in BBS (here: BBS10-mutated patient) [Stoetzel et al., 2006]. C Typical polydactyly found in BBS (here: BBS12-mutated patient) [Stoetzel et al., 2007].