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
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- 作者：Luisa Mackenroth ; Bjö ; rn Fischer-Zirnsak ; Johannes Egerer ; Jochen Hecht ; Tilmann Kallinich ; Werner Stenzel ; Birgit Spors ; Arpad von Moers ; Stefan Mundlos ; Uwe Kornak ; Kerstin Gerhold and Denise Horn
- 关键词：osteogenesis imperfecta ; Ehlers&ndash ; Danlos syndrome ; COL1A1 ; TNXB ; whole exome sequencing
- 刊名：American Journal of Medical Genetics Part A
- 出版年：2016
- 出版时间：April 2016
- 年：2016
- 卷：170
- 期：4
- 页码：1080-1085
- 全文大小：1286K
- ISSN：1552-4833
文摘
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.