Vascular Ehlers-Danlos Syndrome in siblings with biallelic COL3A1 sequence variants and marked clinical variability in the extended family
Vascular Ehlers-Danlos Syndrome in siblings with biallelic COL3A1 sequence variants and marked clinical variability in the extended family
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DOI：
10.1038/ejhg.2014.181
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发表时间：
2015-06-01
影响因子：
5.2
通讯作者：
Byers, Peter H.
中科院分区：
文献类型：
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作者：
Jorgensen, Agnete;Fagerheim, Toril;Byers, Peter H.
血管ehers - danlos综合征（vEDS），也被称为EDS IV型，被认为是一种常染色体显性遗传病，由编码III型前胶原链的COL3A1序列变异引起。我们确定了一个家庭，其中有明显的临床差异，最早的死亡是由于15岁时广泛的主动脉夹层，而其他家庭成员在80多岁时没有并发症。这位先证者出生时患有右内翻足，但在15岁时意外去世之前，其他方面都很健康。他的妹妹，除了符合血管性EDS的征象外，还患有双侧额叶和顶叶多小回症。先证者及其姊妹在不同的等位基因上各有2个COL3A1序列变异，分别是第26外显子c.1786C> A, p.（Arg596*）和第50外显子c.3851G>A, p.（Gly1284Glu）。来自复合杂合子的细胞产生的III型前胶原蛋白数量减少，其所有链都具有异常的电泳流动性。对于零突变或错义突变，双等位基因序列变异的结果明显比杂合变异差，额顶叶多小回症可能是一个附加的表型特征。这种遗传星座为COL3A1序列变异引起的显著家族内临床变异提供了非常罕见的解释。
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.