Broadening the phenotypic spectrum of pathogenic LARP7 variants: two cases with intellectual disability, variable growth retardation and distinct facial features
Broadening the phenotypic spectrum of pathogenic LARP7 variants: two cases with intellectual disability, variable growth retardation and distinct facial features
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DOI：
10.1038/jhg.2015.134
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发表时间：
2016-03-01
影响因子：
3.5
通讯作者：
van de Laar, Ingrid M. B. H.
中科院分区：
文献类型：
--
作者：
Hollink, Iris H. I. M.;Alfadhel, Majid;van de Laar, Ingrid M. B. H.
2012年，Alazami等人描述了一种具有明显面部特征和严重智力残疾的原始侏儒症的新综合征病因。LARP7（非编码RNA 7SK的伴侣）的纯合移码突变，在一个来自沙特阿拉伯的近亲家庭的患者中被发现。到目前为止，最近只报告了另外一名患者。为了进一步描述与LARP7突变相关的表型，我们报告了另外两个来自荷兰和沙特阿拉伯的病例。患者表现为智力障碍，面部特征明显，身材矮小。我们描述了他们的临床特征，并将其与先前报道的患者进行比较。两例均通过诊断性全外显子组测序进行鉴定，检测到两种纯合致病性LARP7变异：荷兰病例的c.1091_1094delCGGT和沙特阿拉伯病例的c.1045_1051dupAAGGATA。这两种变异都通过引入过早的终止密码子导致帧移位，这表明功能丧失可能是疾病机制。本研究独立证实了LARP7缺失引起的综合征。我们的病例拓宽了该综合征的相关临床特征，并有助于描绘LARP7突变的表型谱。
In 2012 Alazami et al. described a novel syndromic cause of primordial dwarfism with distinct facial features and severe intellectual disability. A homozygous frameshift mutation in LARP7, a chaperone of the noncoding RNA 7SK, was discovered in patients from a single consanguineous Saudi family. To date, only one additional patient has recently been described. To further delineate the phenotype associated with LARP7 mutations, we report two additional cases originating from the Netherlands and Saudi Arabia. The patients presented with intellectual disability, distinct facial features and variable short stature. We describe their clinical features and compare them with the previously reported patients. Both cases were identified by diagnostic whole-exome sequencing, which detected two homozygous pathogenic LARP7 variants: c.1091_1094delCGGT in the Dutch case and c.1045_1051dupAAGGATA in the Saudi Arabian case. Both variants are leading to frameshifts with introduction of premature stop codons, suggesting that loss of function is likely the disease mechanism. This study is an independent confirmation of the syndrome due to LARP7 depletion. Our cases broaden the associated clinical features of the syndrome and contribute to the delineation of the phenotypic spectrum of LARP7 mutations.