Alkuraya-Kučinskas syndrome is an autosomal recessive disorder characterized by brain abnormalities associated with cerebral parenchymal underdevelopment, arthrogryposis, club foot and global developmental delay. KIAA1109, a functionally uncharacterized gene is identified as the molecular cause for Alkuraya-Kučinskas syndrome. Most of the reported mutations in KIAA1109 gene result in premature termination of pregnancies or neonatal deaths while a few mutations have been reported in surviving patients with global developmental delay and intellectual disability. To our knowledge, only three surviving patients from two families have been reported with missense variants in KIAA1109. In this study, we describe four surviving patients from two related families (a multiplex family) with global developmental delay and mild to severe intellectual disability with no other systemic manifestations. There were no miscarriages or neonatal deaths reported in these families. X-chromosome exome panel sequencing was carried out in one patient and whole exome sequencing was carried out on the remaining three affected individuals and the unaffected father of the index family. Data analysis was carried out followed by variant filtering and segregation analysis. Sanger sequencing was carried out to validate the segregation of mutation in all four affected siblings and unaffected parents from both families. A novel homozygous missense mutation in a conserved region of KIAA1109 protein was identified. Sanger sequencing confirmed the segregation of mutation in both families in an autosomal recessive fashion. Our study is the second study reporting a KIAA1109 variant in surviving patients with Alkuraya-Kučinskas syndrome. Our study expands the spectrum of phenotypic features and mutations associated with Alkuraya-Kučinskas syndrome.

中文翻译：

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幸存的Alkuraya-Kučinskas综合征患者的KIAA1109基因突变：文献综述。

Alkuraya-Kučinskas综合征是一种常染色体隐性遗传疾病，其特征是与脑实质发育不足，关节软化，俱乐部脚和整体发育延迟有关的脑部异常。KIAA1109，一个功能未知的基因，被确定为Alkuraya-Kučinskas综合征的分子原因。据报道，KIAA1109基因的大多数突变都会导致怀孕或新生儿死亡的提前终止，而存活下来的具有全球性发育迟缓和智力残疾的患者中已有少数突变被报道。据我们所知，在KIAA1109中仅报告了来自两个家庭的三个幸存患者的错义变体。在这个研究中，我们描述了来自两个相关家庭（一个多重家庭）的四个尚存的患者，这些患者具有全球性的发育延迟和轻度至重度智力障碍，没有其他系统性表现。这些家庭没有流产或新生儿死亡的报道。对一名患者进行了X染色体外显子组测序，并对其余三个受影响的个体以及未受影响的索引家族父亲进行了完整的外显子组测序。进行数据分析，然后进行变体过滤和分离分析。进行了桑格测序，以验证两个家庭的所有四个受影响兄弟姐妹和未受影响父母的突变分离。在KIAA1109蛋白的保守区中鉴定了一个新的纯合错义突变。桑格测序证实了两个家族中的突变均以常染色体隐性方式分离。我们的研究是第二项研究，报道了存活的Alkuraya-Kučinskas综合征患者中的KIAA1109变异。我们的研究扩大了与Alkuraya-Kučinskas综合征相关的表型特征和突变的范围。