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

Mackenroth, L.; Fischer-Zirnsak, B.; Egerer, J.; Hecht, J.; Kallinich, T.; Stenzel, W.; Spors, B.; von Moers, A.; Mundlos, S.; Kornak, U.; Gerhold, K.; Horn, D.

doi:10.1002/ajmg.a.37547

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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

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Mundlos, S.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Kornak, U.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Mackenroth, L., Fischer-Zirnsak, B., Egerer, J., Hecht, J., Kallinich, T., Stenzel, W., et al. (2016). 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, 170A(4), 1080-1085. doi:10.1002/ajmg.a.37547.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002E-1C8C-C

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.