EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder.
EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder.
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DOI：
10.1002/ajmg.a.63556
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发表时间：
2024-02
影响因子：
2
通讯作者：
I. Forghani;Steven H. Lang;Matthew J Rodier;Stephanie A Bivona;Alejo A. Morales;Stephan Zuchner;G. Bademci;M. Tekin
中科院分区：
文献类型：
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作者：
I. Forghani;Steven H. Lang;Matthew J Rodier;Stephanie A Bivona;Alejo A. Morales;Stephan Zuchner;G. Bademci;M. Tekin
遗传性结缔组织疾病的表型特征，包括头面部特征、皮肤高度伸展、关节松弛、后凸、蛛网状指、腹股沟疝和与EFEMP1双等位致病变异相关的憩室病，已在四名患者中描述过。对具有相似表型特征的先证者及其母亲的基因组测序显示，两名患者都是停增变种c.1084C>；T的杂合子(p.Arg362*)。成纤维细胞上的互补RNA-seq显示突变的EFEMP1转录水平显著降低。考虑到缺乏其他分子解释，我们推断EFEMP1可能是患者表型的原因。此外，突变等位基因的无义介导的衰退是EFEMP1 mRNA水平降低的主要机制。我们提供了强有力的临床和遗传学证据，证明EFEMP1的单倍性不足是由于胡说八道的药物导致严重的脊柱后凸、关节活动过度、腭弓高和狭窄，以及潜在的严重憩室病。据我们所知，这是第一例常染色体显性显性EFEMP1相关遗传性结缔组织疾病的报告，因此扩大了EFEMP1相关疾病的表型谱。
Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop‐gain variant c.1084C>T (p.Arg362*). Complementary RNA‐seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense‐mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense‐medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1‐associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders.