Smith C, Parboosingh J S, Boycott K M, Bönnemann C G, Mah J K, Lamont R E, Micheil Innes A, Bernier F P
Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
Clin Genet. 2017 Mar;91(3):426-430. doi: 10.1111/cge.12876. Epub 2017 Jan 30.
Mutations in GLE1 cause two recessive subtypes of arthrogryposis multiplex congenita (AMC), a condition characterized by joint contractures at birth, and all previously reported patients died in the perinatal period. GLE1 related AMC has been almost exclusively reported in the Finnish population and is caused by a relatively common pathogenic splicing mutation in that population. Here, we report two non-Finnish brothers with novel compound heterozygous splicing mutations in GLE1, one of whom has survived to 12 years of age. We also demonstrate low levels of residual wild type transcript in fibroblasts from the surviving brother, suggesting that this residual wild-type transcript may contribute to the relatively longer-term survival in this family. We provide a detailed clinical report on the surviving patient, providing the first insight into the natural history of this rare neuromuscular disease. We also suggest that lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn disease (LAAHD), the two AMC subtypes related to GLE1, do not have sufficient clinical or molecular differentiation to be considered allelic disorders. Rather, GLE1 mutations cause a variable spectrum of AMC severity including a non-lethal variant described herein.
GLE1基因的突变会导致先天性多发性关节挛缩症（AMC）的两种隐性亚型，该病的特征是出生时出现关节挛缩，此前报道的所有患者均在围产期死亡。与GLE1相关的AMC几乎仅在芬兰人群中被报道，是由该人群中一种相对常见的致病性剪接突变引起的。在此，我们报告了两名非芬兰籍兄弟，他们在GLE1基因中存在新的复合杂合剪接突变，其中一人已存活至12岁。我们还证明，存活兄弟的成纤维细胞中残留野生型转录本水平较低，这表明这种残留的野生型转录本可能有助于该家族成员相对较长时间的存活。我们提供了关于存活患者的详细临床报告，首次深入了解了这种罕见神经肌肉疾病的自然病史。我们还表明，与GLE1相关的两种AMC亚型，即致死性先天性挛缩综合征1（LCCS1）和伴有前角疾病的致死性关节挛缩症（LAAHD），在临床或分子方面没有足够的差异，不能被视为等位基因疾病。相反，GLE1突变会导致AMC严重程度的可变范围，包括本文所述的非致死性变体。
