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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.
