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Tissue-specific mosaicism for a lethal osteogenesis imperfecta COL1A1 mutation causes mild OI/EDS overlap syndrome

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Abstract
Type I collagen is the predominant protein of connective tissues such as skin and bone. Mutations in the type I collagen genes (COL1A1 and COL1A2) mainly cause osteogenesis imperfecta (OI). We describe a patient with clinical signs of Ehlers-Danlos syndrome (EDS), including fragile skin, easy bruising, recurrent luxations, and fractures resembling mild OI. Biochemical collagen analysis of the patients' dermal fibroblasts showed faint overmodification of the type I collagen bands, a finding specific for structural defects in type I collagen. Bidirectional Sanger sequencing detected an in-frame deletion in exon 44 of COL1A1 (c.3150_3158del), resulting in the deletion of three amino acids (p.Ala1053_Gly1055del) in the collagen triple helix. This COL1A1 mutation was hitherto identified in four probands with lethal OI, and never in EDS patients. As the peaks on the electropherogram corresponding to the mutant allele were decreased in intensity, weperformed next generation sequencing of COL1A1 to study mosaicism in skin and blood. While approximately 9% of the reads originating from fibroblast gDNA harbored the COL1A1 deletion, the deletion was not detected in gDNA from blood. Most likely, the mild clinical symptoms observed in our patient can be explained by the mosaic state of the mutation.
Keywords
EHLERS-DANLOS-SYNDROME, I COLLAGEN, ARTHROCHALASIA TYPE, CHAINS, VIIA, SUBSTITUTION, PROPENSITY, PHENOTYPE, ADULTHOOD, DELETIONS, Ehlers-Danlos syndrome, mosaicism, next generation sequencing, osteogenesis imperfecta

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Chicago
Symoens, Sofie, Wouter Steyaert, Lynn Demuynck, Anne De Paepe, Karin EM Diderich, Fransiska Malfait, and Paul Coucke. 2017. “Tissue-specific Mosaicism for a Lethal Osteogenesis Imperfecta COL1A1 Mutation Causes Mild OI/EDS Overlap Syndrome.” American Journal of Medical Genetics Part A 173 (4): 1047–1050.
APA
Symoens, Sofie, Steyaert, W., Demuynck, L., De Paepe, A., Diderich, K. E., Malfait, F., & Coucke, P. (2017). Tissue-specific mosaicism for a lethal osteogenesis imperfecta COL1A1 mutation causes mild OI/EDS overlap syndrome. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 173(4), 1047–1050.
Vancouver
1.
Symoens S, Steyaert W, Demuynck L, De Paepe A, Diderich KE, Malfait F, et al. Tissue-specific mosaicism for a lethal osteogenesis imperfecta COL1A1 mutation causes mild OI/EDS overlap syndrome. AMERICAN JOURNAL OF MEDICAL GENETICS PART A. 2017;173(4):1047–50.
MLA
Symoens, Sofie, Wouter Steyaert, Lynn Demuynck, et al. “Tissue-specific Mosaicism for a Lethal Osteogenesis Imperfecta COL1A1 Mutation Causes Mild OI/EDS Overlap Syndrome.” AMERICAN JOURNAL OF MEDICAL GENETICS PART A 173.4 (2017): 1047–1050. Print.
@article{8529516,
  abstract     = {Type I collagen is the predominant protein of connective tissues such as skin and bone. Mutations in the type I collagen genes (COL1A1 and COL1A2) mainly cause osteogenesis imperfecta (OI). We describe a patient with clinical signs of Ehlers-Danlos syndrome (EDS), including fragile skin, easy bruising, recurrent luxations, and fractures resembling mild OI. Biochemical collagen analysis of the patients' dermal fibroblasts showed faint overmodification of the type I collagen bands, a finding specific for structural defects in type I collagen. Bidirectional Sanger sequencing detected an in-frame deletion in exon 44 of COL1A1 (c.3150\_3158del), resulting in the deletion of three amino acids (p.Ala1053\_Gly1055del) in the collagen triple helix. This COL1A1 mutation was hitherto identified in four probands with lethal OI, and never in EDS patients. As the peaks on the electropherogram corresponding to the mutant allele were decreased in intensity, weperformed next generation sequencing of COL1A1 to study mosaicism in skin and blood. While approximately 9\% of the reads originating from fibroblast gDNA harbored the COL1A1 deletion, the deletion was not detected in gDNA from blood. Most likely, the mild clinical symptoms observed in our patient can be explained by the mosaic state of the mutation.},
  author       = {Symoens, Sofie and Steyaert, Wouter and Demuynck, Lynn and De Paepe, Anne and Diderich, Karin EM and Malfait, Fransiska and Coucke, Paul},
  issn         = {1552-4825},
  journal      = {AMERICAN JOURNAL OF MEDICAL GENETICS PART A},
  keyword      = {EHLERS-DANLOS-SYNDROME,I COLLAGEN,ARTHROCHALASIA TYPE,CHAINS,VIIA,SUBSTITUTION,PROPENSITY,PHENOTYPE,ADULTHOOD,DELETIONS,Ehlers-Danlos syndrome,mosaicism,next generation sequencing,osteogenesis imperfecta},
  language     = {eng},
  number       = {4},
  pages        = {1047--1050},
  title        = {Tissue-specific mosaicism for a lethal osteogenesis imperfecta COL1A1 mutation causes mild OI/EDS overlap syndrome},
  url          = {http://dx.doi.org/10.1002/ajmg.a.38135},
  volume       = {173},
  year         = {2017},
}

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