Further Evidence of the Importance of RIT1 in Noonan Syndrome
Further Evidence of the Importance of RIT1 in Noonan Syndrome
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DOI：
10.1002/ajmg.a.36722
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发表时间：
2014-11-01
影响因子：
2
通讯作者：
Pereira, Alexandre C.
中科院分区：
文献类型：
--
作者：
Bertola, Debora R.;Yamamoto, Guilherme L.;Pereira, Alexandre C.
努南综合征 (NS) 是一种常染色体显性遗传疾病，包括身材矮小、颈短和/或蹼状、独特的面部特征、心脏异常、隐睾和凝血缺陷。 NS 表现出遗传异质性，与参与 RAS 丝裂原激活蛋白激酶信号转导的突变基因相关。最近，在 180 名日本人中，有 17 人发现了一种新基因 (RIT1) 作为致病基因，这些人对先前已知的 NS 基因呈阴性，并使用外显子组测序（4 名患者）和桑格测序（13 名患者）进行了研究。本研究在 70 名巴西 NS 患者中使用了相同的技术，并鉴定出 6 名患者存在 RIT1 错义突变。因此，我们确认 RIT1 导致大约 10% 的先前已知基因突变呈阴性的患者。表型包括高出生体重、相对大头畸形、左心室肥大和外胚层表现，如卷发、色素沉着过度和手掌和脚底皱纹。身材矮小和胸廓畸形较少发生。大多数携带 RIT1 突变的患者并未表现出明显的智力障碍。由于RIT1在NS患者中突变频率相对较高，且在不同人群中都有发生，我们建议将其添加到Panel基因列表中，通过靶向二代测序进行NS分子诊断。 (c) 2014 年 Wiley 期刊公司。
Noonan syndrome (NS) is an autosomal dominant disorder consisting of short stature, short and/or webbed neck, distinctive facial features, cardiac abnormalities, cryptorchidism, and coagulation defects. NS exhibits genetic heterogeneity, associated with mutated genes that participate in RAS-mitogen-activated protein kinase signal transduction. Recently, a new gene (RIT1) was discovered as the causative gene in 17 of 180 Japanese individuals who were negative for the previously known genes for NS and were studied using exome sequencing (four patients), followed by Sanger sequencing (13 patients). The present study used the same technique in 70 Brazilian patients with NS and identified six with RIT1 missense mutations. Thus, we confirm that RIT1 is responsible for approximately 10% of the patients negative for mutations in the previously known genes. The phenotype includes a high frequency of high birth weight, relative macrocephaly, left ventricular hypertrophy, and ectodermal findings, such as curly hair, hyperpigmentation, and wrinkled palms and soles. Short stature and pectus deformity were less frequent. The majority of patients with a RIT1 mutation did not show apparent intellectual disability. Because of the relatively high frequency of mutations in RIT1 among patients with NS and its occurrence in different populations, we suggest that it should be added to the list of genes included in panels for the molecular diagnosis of NS through targeted next-generation sequencing. (c) 2014 Wiley Periodicals, Inc.