Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants.
Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants.
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DOI：
10.1186/s12881-017-0372-0
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发表时间：
2017-02-01
影响因子：
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通讯作者：
Salvatore F
中科院分区：
文献类型：
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作者：
Esposito G;Testa F;Zacchia M;Crispo AA;Di Iorio V;Capolongo G;Rinaldi L;D'Antonio M;Fioretti T;Iadicicco P;Rossi S;Franzè A;Marciano E;Capasso G;Simonelli F;Salvatore F
Bardet-Biedl综合征（BBS）是一种罕见的遗传性疾病，以视网膜变性、肥胖、多指畸形、学习障碍和肾脏异常为特征。诊断通常在出生时被遗漏，诊断时的中位年龄为9岁。为了进一步了解BBS并提高其诊断和治疗水平，我们评估了BBS分子诊断患者的基因型-表型关系。我们分析了25名符合BBS临床标准的意大利患者的三个常见BBS基因，BBS1， BBS10和BBS2。在12例患者中，我们发现了基因特异性双等位基因变异，从而将基因型与眼科、肾脏和听觉前庭表型相关联。在60%的患者中发现至少一种序列变异。最常见的突变基因是BBS1，其次是BBS10。在我们发现的17个序列变异中，有11个以前没有与BBS相关。在12例患者中，我们发现了双等位基因致病变异；他们患有色素性视网膜炎，并伴有早期视力障碍。然而，与BBS10变异患者相比，BBS1患者视网膜营养不良的严重程度较轻。总的来说，我们发现肾脏畸形和功能障碍的患病率很高。值得注意的是，BBS10变异的患者肾功能受损最严重，导致肾功能严重下降。所有接受听力-前庭评估的患者耳蜗外毛细胞均出现功能障碍，证实存在听力缺陷。BBS1、BBS2和BBS10是意大利BBS患者的主要致病基因。BBS10在肾、眼和听庭表型方面与较差的结果相关。耳蜗功能障碍应包括在BBS的标志之一。本文的在线版本（doi:10.1186/s12881-017-0372-0）包含补充材料，可供授权用户使用。
Bardet-Biedl syndrome (BBS) is a rare genetic disorder that features retinal degeneration, obesity, polydactyly, learning disabilities and renal abnormalities. The diagnosis is often missed at birth, the median age at diagnosis being 9 years. In the attempt to shed light on BBS and improve its diagnosis and treatment, we evaluated the genotype-phenotype relationship in patients with a molecular diagnosis of BBS. We analyzed three common BBS genes, BBS1, BBS10 and BBS2, in 25 Italian patients fulfilling the clinical criteria of BBS. In 12 patients, we identified gene-specific biallelic variants and thus correlated genotype to the ophthalmic, renal and audio-vestibular phenotypes. At least one sequence variant was found in 60% of patients. The most common mutated gene was BBS1 followed by BBS10. Of the 17 sequence variants we found, 11 have not previously been associated with BBS. In 12 patients, we identified biallelic pathogenic variants; they had retinitis pigmentosa with early onset of visual impairment. However, retinal dystrophy was less severe in patients with BBS1 than in those with BBS10 variants. Overall, we found a high prevalence of renal dysmorphism and dysfunction. Notably, patients with BBS10 variants had the most severe renal impairment, which resulted in a critical decline in renal function. All the patients who underwent audio-vestibular evaluation had dysfunction of the cochlear outer hair cells, thus confirming the presence of hearing defects. BBS1, BBS2 and BBS10 are major causative genes in Italian BBS patients. BBS10 was associated with the worse outcome in terms of the renal, ocular and audiovestibular phenotypes. Cochlear dysfunction should be included among the hallmarks of BBS. The online version of this article (doi:10.1186/s12881-017-0372-0) contains supplementary material, which is available to authorized users.