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Clin Genet. 2017 Mar;91(3):426-430. doi: 10.1111/cge.12876. Epub 2017 Jan 30.

Expansion of the GLE1-associated arthrogryposis multiplex congenita clinical spectrum.

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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.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD, USA.
Division of Neurology, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.


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.


RNA metabolism; exome; infantile SMA; mRNA export; motor neuron disease; spinal muscular atrophy

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