Jørgensen Agnete, Fagerheim Toril, Rand-Hendriksen Svend, Lunde Per I, Vorren Torgrim O, Pepin Melanie G, Leistritz Dru F, Byers Peter H
Division of Child and Adolescent Health, Medical Genetics Department, University Hospital of North Norway, Tromsø, Norway.
TRS, National Resource Centre for Rare Disorders, Sunnaas Rehabilitation Hospital, Nesoddtangen, Norway.
Eur J Hum Genet. 2015 Jun;23(6):796-802. doi: 10.1038/ejhg.2014.181. Epub 2014 Sep 10.
Vascular Ehlers-Danlos Syndrome (vEDS), also known as EDS type IV, is considered to be an autosomal dominant disorder caused by sequence variants in COL3A1, which encodes the chains of type III procollagen. We identified a family in which there was marked clinical variation with the earliest death due to extensive aortic dissection at age 15 years and other family members in their eighties with no complications. The proband was born with right-sided clubfoot but was otherwise healthy until he died unexpectedly at 15 years. His sister, in addition to signs consistent with vascular EDS, had bilateral frontal and parietal polymicrogyria. The proband and his sister each had two COL3A1 sequence variants, c.1786C>T, p.(Arg596*) in exon 26 and c.3851G>A, p.(Gly1284Glu) in exon 50 on different alleles. Cells from the compound heterozygote produced a reduced amount of type III procollagen, all the chains of which had abnormal electrophoretic mobility. Biallelic sequence variants have a significantly worse outcome than heterozygous variants for either null mutations or missense mutations, and frontoparietal polymicrogyria may be an added phenotype feature. This genetic constellation provides a very rare explanation for marked intrafamilial clinical variation due to sequence variants in COL3A1.
血管型埃勒斯-当洛综合征（vEDS），也称为IV型埃勒斯-当洛综合征，被认为是一种常染色体显性疾病，由编码III型前胶原链的COL3A1基因序列变异引起。我们鉴定了一个家族，其中存在明显的临床变异，最早在15岁时因广泛的主动脉夹层死亡，而其他家族成员八十多岁却没有并发症。先证者出生时患有右侧马蹄内翻足，但在15岁意外死亡前一直健康。他的姐姐除了有与血管型埃勒斯-当洛综合征相符的体征外，还患有双侧额顶叶多小脑回畸形。先证者和他的姐姐各自有两个COL3A1基因序列变异，分别位于不同等位基因的第26外显子的c.1786C>T，p.(Arg596*)和第50外显子的c.3851G>A，p.(Gly1284Glu)。复合杂合子的细胞产生的III型前胶原量减少，其所有链的电泳迁移率均异常。对于无义突变或错义突变，双等位基因序列变异的预后明显比杂合子变异差，额顶叶多小脑回畸形可能是一个额外的表型特征。这种基因组合为COL3A1基因序列变异导致的家族内明显临床变异提供了一个非常罕见的解释。
