We have previously reported on a consanguineous family where 2 siblings, a girl and a boy, presented with tall stature, long and triangular faces, prominent forehead, telecanthus, ptosis, everted lower eyelids, downslanting palpebral fissures, large ears, high arched palate, long arm span, arachnodactyly, advanced bone age, joint laxity, pectus excavatum, inguinal hernia, and myopia, suggestive of a new subtype of connective tissue disorder (Megarbane et al. AJMG, 2012; 158(A)5: 1185–1189). On clinical follow-up, both patients had multiple inguinal, crural, and abdominal herniae, intestinal occlusions, several huge diverticula throughout the gut and the bladder, and rectal prolapse. In addition, the girl had a mild hearing impairment, and the boy a left diaphragmatic hernia.

Here we describe the molecular characterization of this disorder using Whole Exome Sequencing, revealing, in both siblings, a novel homozygous missense variant in the EFEMP1 gene, c.163T > C; p.(Cys55Arg) whose homozygous by descent, autosomal recessive transmission was confirmed through segregation analysis by Sanger sequencing. In addition, the girl exhibited a homozygous mutation in the MYO3A gene, c.1370_1371delGA; p.(Arg457Asnfs*25), associated with non-syndromic deafness. The siblings were also found to harbor a homozygous nonsense variant in the VCPKMT gene. We review the literature and discuss our updated clinical and molecular findings that suggest EFEMP1 to be the probable candidate gene implicated in this novel connective tissue disease.

我们之前曾报道过一个近亲家庭，其中两个兄弟姐妹（一个女孩和一个男孩）身材高大，长而三角形的脸，突出的前额，喙突，上睑下垂，下眼睑外翻，睑裂向下倾斜，大耳朵，高弓形pa，手臂长跨度，蜘蛛突触，晚期骨龄，关节松弛，眼底凹陷，腹股沟疝和近视，提示结缔组织病是一种新的亚型（Megarbane等，AJMG，2012； 158（A）5：1185-1189） 。在临床随访中，两名患者均患有多处腹股沟，腹股沟和腹部疝，肠管阻塞，整个肠道和膀胱有数个巨大憩室以及直肠脱垂。此外，女孩轻度听力障碍，男孩左left肌疝。

在这里，我们描述了使用全外显子组测序对这种疾病的分子特征，在两个兄弟姐妹中都揭示了EFEMP1基因中的一个纯合子错义变体，c.163T>C。p。（Cys55Arg）其血统是纯合的，常染色体隐性传播是通过Sanger测序的分离分析证实的。另外，该女孩在MYO3A基因c.1370_1371delGA中表现出纯合突变。p。（Arg457Asnfs * 25），与非综合征性耳聋有关。还发现该兄弟姐妹在VCPKMT基因中具有纯合的无意义变异。我们回顾文献并讨论我们的更新的临床和分子发现，这些结果提示EFEMP1 可能与这种新型结缔组织病有关。