Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome
Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome
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DOI：
10.1007/s00439-013-1295-2
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发表时间：
2013-08-01
期刊：
影响因子：
5.3
通讯作者：
Wieczorek, D.
中科院分区：
文献类型：
--
作者：
Czeschik, J. C.;Voigt, C.;Wieczorek, D.
Nager综合征（MIM #154400）是最著名的轴前肢面骨发育不全，主要特征是颅面和轴前肢体异常。颅面畸形主要包括睑裂下斜、颧骨发育不全、小颌畸形、外耳畸形和腭裂。肢体轴前缺损的特点是桡骨和拇指发育不全或发育不全、双拇指和桡尺近端骨性连接。SF 3B 4（MIM *605593）的单倍不足，其编码前mRNA剪接体复合物的组分SAP 49，最近已被确定为Nager综合征的潜在原因。在我们的研究中，我们进行了外显子组测序的两个和桑格测序的SF 3B 4在另外10个以前未报告的临床诊断为Nager综合征的患者，包括一个家族性病例。我们在12例患者中的7例中发现了SF 3B 4杂合突变。七个突变中有四个被证明是新生的;在三个个体中，父母双方的DNA都不可用。未发现家族性突变。三个突变是无义突变，三个是移码突变，一个T > C转换破坏了翻译起始信号。在四个SF 3B 4阴性家族中的三个中，分析了EFTUD 2，但未鉴定出致病性变体。我们的研究结果表明，SF 3B 4基因突变的约一半的患者与临床诊断的Nager综合征，进一步支持这种情况下的遗传异质性。
Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.