Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta.
Adolescent
Adult
Bone Density
/ genetics
Child
Child, Preschool
Collagen Type I
/ genetics
Collagen Type I, alpha 1 Chain
Female
Genetic Association Studies
Genetic Variation
High-Throughput Nucleotide Sequencing
Humans
Infant
Japan
Male
Mutation
Osteogenesis Imperfecta
/ genetics
Sequence Analysis, DNA
Young Adult
Fracture
Genotype-phenotype correlation
Next-generation sequencing
Osteogenesis imperfecta
Short stature
Type I collagen
Journal
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
ISSN: 1433-2965
Titre abrégé: Osteoporos Int
Pays: England
ID NLM: 9100105
Informations de publication
Date de publication:
Nov 2019
Nov 2019
Historique:
received:
12
03
2019
accepted:
26
06
2019
pubmed:
1
8
2019
medline:
17
6
2020
entrez:
1
8
2019
Statut:
ppublish
Résumé
To elucidate mutation spectrum and genotype-phenotype correlations in Japanese patients with OI, we conducted comprehensive genetic analyses using NGS, as this had not been analyzed comprehensively in this patient population. Most mutations were located on COL1A1 and COL1A2. Glycine substitutions in COL1A1 resulted in the severe phenotype. Most cases of osteogenesis imperfecta (OI) are caused by mutations in COL1A1 or COL1A2, which encode α chains of type I collagen. However, mutations in at least 16 other genes also cause OI. The mutation spectrum in Japanese patients with OI has not been comprehensively analyzed, as it is difficult to identify using classical Sanger sequencing. In this study, we aimed to reveal the mutation spectrum and genotype-phenotype correlations in Japanese patients with OI using next-generation sequencing (NGS). We designed a capture panel for sequencing 15 candidate OI genes and 19 candidate genes that are associated with bone fragility or Wnt signaling. Using NGS, we examined 53 Japanese patients with OI from unrelated families. Pathogenic mutations were detected in 43 out of 53 individuals. All mutations were heterozygous. Among the 43 individuals, 40 variants were identified including 15 novel mutations. We found these mutations in COL1A1 (n = 30, 69.8%), COL1A2 (n = 12, 27.9%), and IFITM5 (n = 1, 2.3%). Patients with glycine substitution on COL1A1 had a higher frequency of fractures and were more severely short-statured. Although no significant genotype-phenotype correlation was observed for bone mineral density, the trabecular bone score was significantly lower in patients with glycine substitutions. We identified pathogenic mutations in 81% of our Japanese patients with OI. Most mutations were located on COL1A1 and COL1A2. This study revealed that glycine substitutions on COL1A1 resulted in the severe phenotype among Japanese patients with OI.
Identifiants
pubmed: 31363794
doi: 10.1007/s00198-019-05076-6
pii: 10.1007/s00198-019-05076-6
pmc: PMC7083816
doi:
Substances chimiques
Collagen Type I
0
Collagen Type I, alpha 1 Chain
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2333-2342Commentaires et corrections
Type : ErratumIn
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