Identification of two novel mutations in the NOG gene associated with congenital stapes ankylosis and symphalangism
Identification of two novel mutations in the NOG gene associated with congenital stapes ankylosis and symphalangism
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DOI：
10.1038/jhg.2014.97
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发表时间：
2015-01-01
影响因子：
3.5
通讯作者：
Suzuki, Mikio
中科院分区：
文献类型：
--
作者：
Ganaha, Akira;Kaname, Tadashi;Suzuki, Mikio
在这项研究中，我们描述了三个不相关的日本听力损失和指关节粘连的患者，根据临床特征，他们分别被诊断为近端指关节粘连（SYM 1）、非典型多发性骨性结合综合征（非典型SYNS 1）和镫骨强直伴宽拇指和脚趾（SABTT）。中耳的手术结果在患者中相似。通过下一代和桑格测序分析，我们鉴定了两个新的突变，c.559C>G（p.P178A）和c. 682 T>A（p.C228S），分别在SYM 1和非典型SYNS 1家族中。在SABTT家族中NOG、GDF 5或FGF 9基因的蛋白编码区、外显子-内含子边界或启动子区未发现致病性变化。这些阴性分子数据表明，SYNS 1可能存在进一步的遗传异质性，至少涉及一个额外的基因。镫骨切开术导致所有患者长期听力良好，表明基因型和手术结果之间没有相关性。鉴于这些综合征的临床特征在我们的患者和分子研究结果的重叠，诊断术语“NOG相关的共指畸形谱系障碍（NOG-SSD）”主张和一个未知的基因可能是这种疾病的原因。
In this study, we describe three unrelated Japanese patients with hearing loss and symphalangism who were diagnosed with proximal symphalangism (SYM1), atypical multiple synostosis syndrome (atypical SYNS1) and stapes ankylosis with broad thumb and toes (SABTT), respectively, based on the clinical features. Surgical findings in the middle ear were similar among the patients. By next-generation and Sanger sequencing analyses, we identified two novel mutations, c.559C>G (p. P178A) and c. 682T>A (p. C228S), in the SYM1 and atypical SYNS1 families, respectively. No pathogenic changes were found in the protein-coding regions, exon-intron boundaries or promoter regions of the NOG, GDF5 or FGF9 genes in the SABTT family. Such negative molecular data suggest there may be further genetic heterogeneity underlying SYNS1, with the involvement of at least one additional gene. Stapedotomy resulted in good hearing in all patients over the long term, indicating no correlation between genotype and surgical outcome. Given the overlap of the clinical features of these syndromes in our patients and the molecular findings, the diagnostic term 'NOG-related-symphalangism spectrum disorder (NOG-SSD)' is advocated and an unidentified gene may be responsible for this disorder.