Jaya Punetha1,2, Akanchha Kesari1, Eric P Hoffman1,2, Monika Gos3, Anna Kamińska4, Anna Kostera-Pruszczyk4, Irena Hausmanowa-Petrusewicz5, Ying Hu6, Yaqun Zou6, Carsten G Bönnemann6, Maria JȨdrzejowska5,7. 1. Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA. 2. Department of Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA. 3. Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. 4. Department of Neurology, Medical University of Warsaw, Warsaw, Poland. 5. Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. 6. National Institute of Neurological Disorders and Stroke/NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA. 7. Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
Abstract
INTRODUCTION: Mutations in the COL12A1 (collagen, type XII, alpha 1) gene have been described in a milder Bethlem-like myopathy in 6 patients from 3 families (dominant missense), and in a severe congenital form with failure to attain ambulation in 2 patients in a single pedigree (recessive loss-of-function). METHODS: We describe an 8-year-old girl of Polish origin who presented with profound hypotonia and joint hyperlaxity at birth after a pregnancy complicated by oligohydramnios and intrauterine growth retardation. RESULTS: We identified a novel, potentially pathogenic heterozygous missense COL12A1 c.8329G>C (p.Gly2777Arg) variant using a targeted sequencing panel. Patient fibroblast studies confirmed intracellular retention of the COL12A1 protein, consistent with a dominant-negative mutation. CONCLUSIONS: As our patient showed a more intermediate phenotype, this case expands the phenotypic spectrum for COL12A1 disorders. So far, COL12A1 disorders seem to cover much of the severity range of an Ehlers-Danlos/Bethlem-like myopathy overlap syndrome associated with both connective tissue abnormalities and muscle weakness. Muscle Nerve 55: 277-281, 2017.
INTRODUCTION: Mutations in the COL12A1 (collagen, type XII, alpha 1) gene have been described in a milder Bethlem-like myopathy in 6 patients from 3 families (dominant missense), and in a severe congenital form with failure to attain ambulation in 2 patients in a single pedigree (recessive loss-of-function). METHODS: We describe an 8-year-old girl of Polish origin who presented with profound hypotonia and joint hyperlaxity at birth after a pregnancy complicated by oligohydramnios and intrauterine growth retardation. RESULTS: We identified a novel, potentially pathogenic heterozygous missense COL12A1 c.8329G>C (p.Gly2777Arg) variant using a targeted sequencing panel. Patient fibroblast studies confirmed intracellular retention of the COL12A1 protein, consistent with a dominant-negative mutation. CONCLUSIONS: As our patient showed a more intermediate phenotype, this case expands the phenotypic spectrum for COL12A1 disorders. So far, COL12A1 disorders seem to cover much of the severity range of an Ehlers-Danlos/Bethlem-like myopathy overlap syndrome associated with both connective tissue abnormalities and muscle weakness. Muscle Nerve 55: 277-281, 2017.
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