Biallelic variants in SLC35C1 as a cause of isolated short stature with intellectual disability.,Journal of Human Genetics

当前位置： X-MOL 学术 › J. Hum. Genet. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Biallelic variants in SLC35C1 as a cause of isolated short stature with intellectual disability.
Journal of Human Genetics ( IF 2.6 ) Pub Date : 2020-04-21 , DOI: 10.1038/s10038-020-0764-4
Karen M Knapp ₁ , Rebecca Luu ₁ , Melissa Baerenfaenger ₂ , Fokje Zijlstra ₃ , Hans J C T Wessels ₃ , Danielle Jenkins ₁ , Dirk J Lefeber _{2,

3} , Katherine Neas ₄ , Louise S Bicknell ₁

Affiliation

Variants in SLC35C1 underlie leucocyte adhesion deficiency (LADII) or congenital disorder of glycosylation type 2c (CDGIIc), an autosomal recessive disorder of fucosylation. This immunodeficiency syndrome is generally characterized by severe recurrent infections, Bombay blood group, reduced growth and intellectual disability (ID). Features are all caused by an inability to generate key fucosylated molecules due to a defective transport of GDP-fucose into the Golgi. Here we report the use of exome sequencing to identify biallelic variants in SLC35C1 (c.501_503delCTT, p.(Phe168del) and c.891T > G, p.(Asn297Lys)) in an individual with short stature and ID. Retrospective clinical examination based on the genetic findings revealed increased otitis media as the only immunological feature present in this child. Biochemical analysis of patient serum identified a clear but mild decrease in protein fucosylation. Modelling all described missense mutations on a SLC35C1 protein model showed pathogenic substitutions localise to close to the dimer interface, providing insight into the possible pathophysiology of non-synonymous causative variants identified in patients. Our evidence confirms this is the second family presenting with only a subset of features and broadens the clinical presentation of this syndrome. Of note, both families segregated a common allele (p.Phe168del), suggesting there could be an associated genotype-phenotype relationship for specific variants. Based on two out of 14 reported families not presenting with the characteristic features of SLC35C1-CDG, we suggest there is clinical utility in considering this gene in patients with short stature and ID.

中文翻译：

SLC35C1中的双等位基因变异是导致智障的孤立身材矮小的原因。

SLC35C1的变体是白细胞粘附缺乏症（LADII）或2c型糖基化先天性疾病（CDGIIc）的基础，后者是岩藻糖基化的常染色体隐性疾病。这种免疫缺陷综合症的特征通常是严重的反复感染，孟买血型，生长减少和智力残疾（ID）。所有这些都是由于GDP-岩藻糖向高尔基体运输不良而无法生成关键的岩藻糖基化分子所致。在这里我们报告使用外显子组测序来鉴定身材矮小且身材矮小的个体中SLC35C1（c.501_503delCTT，p。（Phe168del）和c.891T> G，p。（Asn297Lys））中的双等位基因变异。根据遗传学发现进行的回顾性临床检查显示，中耳炎增加是该儿童中唯一的免疫学特征。对患者血清的生化分析发现蛋白岩藻糖基化明显但轻度降低。在SLC35C1蛋白模型上对所有描述的错义突变进行建模，显示病原体替代定位在接近二聚体界面的位置，从而提供了对患者中识别出的非同义致病性变体可能的病理生理学的认识。我们的证据证实这是仅表现一部分特征的第二家族，并且扩大了该综合征的临床表现。值得注意的是，两个家族均分离出一个共同的等位基因（p.Phe168del），这表明特定变体可能存在相关的基因型与表型关系。基于14个报告的家族中的2个不具有SLC35C1-CDG特征的家族，

更新日期：2020-04-24

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南