An overlapping phenotype of Osteogenesis imperfecta and Ehlers-Danlos syndrome due to a heterozygous mutation in COL1A1 and biallelic missense variants in TNXB identified by whole exome sequencing

American Journal of Medical Genetics. Part a
Luisa MackenrothDenise Horn

Abstract

Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G > A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin-X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype.

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Citations

Jun 9, 2016·American Journal of Medical Genetics. Part a·Alina KurolapHagit N Baris
Mar 5, 2019·Molecular Genetics & Genomic Medicine·Mingyuan WangLamei Yuan
Apr 16, 2020·The Journal of Clinical Endocrinology and Metabolism·Yinjie GaoXueyan Wu
Jun 21, 2019·Intractable & Rare Diseases Research·Yanqin LuJinxiang Han
Mar 13, 2020·Current Osteoporosis Reports·Shuaa Basalom, Frank Rauch
Aug 31, 2020·Connective Tissue Research·Rai-Hseng HsuNi-Chung Lee

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