Schaefer E, Zaloszyc A, Lauer J, Durand M, Stutzmann F, Perdomo-Trujillo Y, Redin C, Bennouna Greene V, Toutain A, Perrin L, Gérard M, Caillard S, Bei X, Lewis R A, Christmann D, Letsch J, Kribs M, Mutter C, Muller J, Stoetzel C, Fischbach M, Marion V, Katsanis N, Dollfus H
Laboratoire de Génétique Médicale EA 3949, Equipe Avenir-Inserm, Faculté de Médecine de Strasbourg, Université de Strasbourg, Strasbourg.
Mol Syndromol. 2011 Sep;1(6):273-281. doi: 10.1159/000331268. Epub 2011 Sep 14.
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.
纤毛病是由与初级纤毛的生物发生和功能相关的基因突变引起的一组不断扩大的疾病。巴德-比德尔综合征（BBS）是一种典型的纤毛病，其特征为进行性视网膜变性、肥胖、多指畸形、认知障碍、肾脏异常和性腺功能减退。最近在患有肾单位肾痨和视网膜变性（Senior-Loken综合征；SLS）的患者中发现了SDCCAG8（NPHP10）基因的突变。鉴于已知纤毛病基因之间存在表型和遗传重叠，我们推测SDCCAG8基因的突变也可能导致更严重的多系统纤毛病等位基因。我们对两个独立的BBS队列进行了遗传和表型分析。在进行突变筛查后，我们对5个发生SDCCAG8基因突变的家系（3个纯合突变和2个复合杂合突变）进行了详细的表型分析，并对两个队列进行了统计分析，以研究该位点突变可能存在的表型-基因型相关性。所有发生SDCCAG8基因突变的患者均符合BBS的诊断标准（视网膜变性、肥胖、认知缺陷、肾衰竭、性腺功能减退）。有趣的是，原发性SDCCAG8基因突变的患者均无多指畸形，而多指畸形是BBS常见但并非必然出现的特征。相反，这些患者表现出早发性肾衰竭、肥胖以及反复的肺部和耳鼻喉感染。将这些家系的表型与我们整个BBS队列进行比较表明，肾功能损害和无多指畸形与致病性SDCCAG8基因突变显著相关。因此，在我们合并的队列中，SDCCAG8基因突变足以导致1%-2%的患者患BBS，并将该基因定义为第16个BBS位点（BBS16）。无多指畸形以及与早期肾衰竭的明显完全显性关联代表了BBS中首个重要的基因型-表型相关性，这可能是表型驱动的优先筛查指标，并为特定患者的管理提供参考。
