Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas‐Papas and CHAND syndromes
Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas‐Papas and CHAND syndromes
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DOI：
10.1002/ajmg.a.37233
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发表时间：
2015-11
影响因子：
2
通讯作者：
Benjamin Gollasch;F. B. Basmanav;A. Nanda;G. Fritz;H. Mahmoudi;H. Thiele;Maria Wehner;S. Wolf;J. Altmüller;P. Nürnberg;J. Frank;R. Betz
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文献类型：
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作者：
Benjamin Gollasch;F. B. Basmanav;A. Nanda;G. Fritz;H. Mahmoudi;H. Thiele;Maria Wehner;S. Wolf;J. Altmüller;P. Nürnberg;J. Frank;R. Betz
3名来自科威特近亲的儿童表现为睑球粘连、头发稀疏卷曲和指甲发育不全，提示CHAND综合征（OMIM 214350），属于外胚层发育不良的异质性谱系。在排除TP 63中的致病性突变后，我们进行了纯合性作图，然后对一个受影响的个体进行了外显子组测序。我们最初在连锁区域中鉴定了三个纯合突变，分别位于PWP 2、MX2和RIPK 4。最近，在Bartsocas-Papas综合征（OMIM 263650）中报告了RIPK 4的突变，该综合征显示出与本文研究的受影响个体中观察到的表型重叠的临床症状。随后对受影响和未受影响的家族成员的分析表明，RIPK 4中的突变c.850G>A（p.Glu284Lys）与疾病表型完全分离，符合常染色体隐性遗传模式，因此支持该变体的致病性。然而，有趣的是，我们的患者没有唇腭裂，这是Bartsocas-Papas综合征的常见特征。而在Bartsocas-Papas综合征中，错义突变通常位于RIPK 4的丝氨酸/苏氨酸激酶内，在我们家族中检测到的突变位于激酶结构域之外，这可以解释较温和的表型。我们的数据提出了一个问题，如果CHAND综合征确实是一个独特的实体。或者，CHAND和Bartsocas-Papas综合征可能是等位基因疾病，或者RIPK 4突变可能赋予不同程度的表型严重程度，这取决于它们在功能重要域内或外的定位。我们的研究结果表明，仅根据流行的临床症状做出准确的诊断是具有挑战性的。© 2015威利期刊公司.
Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas‐Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non‐affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingly, however, our patients did not have cleft lip/palate, a common feature encountered in Bartsocas‐Papas syndrome. Whereas in Bartsocas‐Papas syndromes missense mutations are usually located within the serin/threonin kinase of RIPK4, the mutation detected in our family resides just outside of the kinase domain, which could explain the milder phenotype. Our data raise the question if CHAND syndrome indeed is a distinct entity. Alternatively, CHAND and Bartsocas‐Papas syndrome might be allelic disorders or RIPK4 mutations could confer varying degrees of phenotypic severity, depending on their localization within or outside functionally important domains. Our findings indicate that making an accurate diagnosis based only on the prevailing clinical symptoms is challenging. © 2015 Wiley Periodicals, Inc.