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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

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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-1C8C-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-1C8D-A
Genre: Journal Article

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Mackenroth, L., Author
Fischer-Zirnsak, B., Author
Egerer, J., Author
Hecht, J., Author
Kallinich, T., Author
Stenzel, W., Author
Spors, B., Author
von Moers, A., Author
Mundlos, S.1, Author              
Kornak, U.1, Author              
Gerhold, K., Author
Horn, D., Author
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: Alleles Collagen Type I/*genetics/metabolism DNA Mutational Analysis Ehlers-Danlos Syndrome/*diagnosis/*genetics Exome *Heterozygote High-Throughput Nucleotide Sequencing Humans Immunohistochemistry Infant Male *Mutation Osteogenesis Imperfecta/*diagnosis/*genetics Pedigree *Phenotype Tenascin/*genetics Col1a1 Ehlers-Danlos syndrome Tnxb osteogenesis imperfecta whole exome sequencing
 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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Language(s): eng - English
 Dates: 2016-01-222016-04
 Publication Status: Published in print
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 Identifiers: DOI: 10.1002/ajmg.a.37547
ISSN: 1552-4833 (Electronic)1552-4825 (Print)
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Title: American Journal of Medical Genetics Part A
Source Genre: Journal
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Publ. Info: Hoboken, N.J. : Wiley-Liss
Pages: - Volume / Issue: 170A (4) Sequence Number: - Start / End Page: 1080 - 1085 Identifier: ISSN: 1552-4825
CoNE: /journals/resource/954925476465