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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
Author(s) -
Mackenroth Luisa,
FischerZirnsak Björn,
Egerer Johannes,
Hecht Jochen,
Kallinich Tilmann,
Stenzel Werner,
Spors Birgit,
von Moers Arpad,
Mundlos Stefan,
Kornak Uwe,
Gerhold Kerstin,
Horn Denise
Publication year - 2016
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.37547
Subject(s) - missense mutation , ehlers–danlos syndrome , osteogenesis imperfecta , exome sequencing , frameshift mutation , joint hypermobility , genetics , mutation , medicine , hypotonia , sanger sequencing , phenotype , biology , pathology , anatomy , gene
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. © 2016 Wiley Periodicals, Inc.