Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica

Ryojun Takeda, Masaki Takagi, Hiroyuki Shinohara, Hiroshi Futagawa, Satoshi Narumi, Tomonobu Hasegawa, Gen Nishimura, Hiroshi Yoshihashi

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Geroderma osteodysplastica (GO) is a subtype of cutis laxa syndrome characterized by congenital wrinkly skin, a prematurely aged face, extremely short stature, and osteoporosis leading to recurrent fractures. GO exhibits an autosomal recessive inheritance pattern and is caused by loss-of-function mutations in GORAB, which encodes a protein important for Golgi-related transport. Using whole exome sequencing, we identified novel compound heterozygous nonsense mutations in the GORAB in a GO patient.The patient was a 14-year-old Japanese boy. Wrinkled skin and joint laxity were present at birth. At 1 year of age, he was clinically diagnosed with cutis laxa syndrome based on recurrent long bone fractures and clinical features, including wrinkled skin, joint laxity, and a distinctive face. He did not show retarded gross motor and cognitive development. At 11 years of age, he was treated with oral bisphosphonate and vitamin D owing to recurrent multiple spontaneous fractures of the vertebral and extremity bones associated with a low bone mineral density (BMD). Bisphosphonate treatment improved his BMD and fracture rate. Whole exome sequencing revealed two novel compound heterozygous nonsense mutations in the GORAB gene (p.Arg60* and p.Gln124*), and the diagnosis of GO was established. GO is a rare connective tissue disorder. Approximately 60 cases have been described to date, and this is the first report of a patient from Japan. Few studies have reported the effects of bisphosphonate treatment in GO patients with recurrent spontaneous fractures. Based on this case study, we hypothesize that oral bisphosphonate and vitamin D are effective and safe treatment options for the management of recurrent fractures in GO patients. It is important to establish a precise diagnosis of GO to prevent recurrent fractures and optimize treatment plans.

Original languageEnglish
JournalEuropean Journal of Medical Genetics
DOIs
Publication statusAccepted/In press - 2017

Fingerprint

Exome
Mutation
Diphosphonates
Cutis Laxa
Joint Instability
Spontaneous Fractures
Nonsense Codon
Bone Fractures
Vitamin D
Bone Density
Skin
Inheritance Patterns
Gerodermia osteodysplastica
Therapeutics
Connective Tissue
Osteoporosis
Japan
Extremities
Parturition
Bone and Bones

Keywords

  • Bisphosphonate
  • Cutis laxa syndrome
  • Geroderma osteodysplastica
  • Osteoporosis
  • Whole exome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica. / Takeda, Ryojun; Takagi, Masaki; Shinohara, Hiroyuki; Futagawa, Hiroshi; Narumi, Satoshi; Hasegawa, Tomonobu; Nishimura, Gen; Yoshihashi, Hiroshi.

In: European Journal of Medical Genetics, 2017.

Research output: Contribution to journalArticle

Takeda, Ryojun ; Takagi, Masaki ; Shinohara, Hiroyuki ; Futagawa, Hiroshi ; Narumi, Satoshi ; Hasegawa, Tomonobu ; Nishimura, Gen ; Yoshihashi, Hiroshi. / Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica. In: European Journal of Medical Genetics. 2017.
@article{f544d98633294464aafef10667fce54b,
title = "Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica",
abstract = "Geroderma osteodysplastica (GO) is a subtype of cutis laxa syndrome characterized by congenital wrinkly skin, a prematurely aged face, extremely short stature, and osteoporosis leading to recurrent fractures. GO exhibits an autosomal recessive inheritance pattern and is caused by loss-of-function mutations in GORAB, which encodes a protein important for Golgi-related transport. Using whole exome sequencing, we identified novel compound heterozygous nonsense mutations in the GORAB in a GO patient.The patient was a 14-year-old Japanese boy. Wrinkled skin and joint laxity were present at birth. At 1 year of age, he was clinically diagnosed with cutis laxa syndrome based on recurrent long bone fractures and clinical features, including wrinkled skin, joint laxity, and a distinctive face. He did not show retarded gross motor and cognitive development. At 11 years of age, he was treated with oral bisphosphonate and vitamin D owing to recurrent multiple spontaneous fractures of the vertebral and extremity bones associated with a low bone mineral density (BMD). Bisphosphonate treatment improved his BMD and fracture rate. Whole exome sequencing revealed two novel compound heterozygous nonsense mutations in the GORAB gene (p.Arg60* and p.Gln124*), and the diagnosis of GO was established. GO is a rare connective tissue disorder. Approximately 60 cases have been described to date, and this is the first report of a patient from Japan. Few studies have reported the effects of bisphosphonate treatment in GO patients with recurrent spontaneous fractures. Based on this case study, we hypothesize that oral bisphosphonate and vitamin D are effective and safe treatment options for the management of recurrent fractures in GO patients. It is important to establish a precise diagnosis of GO to prevent recurrent fractures and optimize treatment plans.",
keywords = "Bisphosphonate, Cutis laxa syndrome, Geroderma osteodysplastica, Osteoporosis, Whole exome sequencing",
author = "Ryojun Takeda and Masaki Takagi and Hiroyuki Shinohara and Hiroshi Futagawa and Satoshi Narumi and Tomonobu Hasegawa and Gen Nishimura and Hiroshi Yoshihashi",
year = "2017",
doi = "10.1016/j.ejmg.2017.08.002",
language = "English",
journal = "European Journal of Medical Genetics",
issn = "1769-7212",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica

AU - Takeda, Ryojun

AU - Takagi, Masaki

AU - Shinohara, Hiroyuki

AU - Futagawa, Hiroshi

AU - Narumi, Satoshi

AU - Hasegawa, Tomonobu

AU - Nishimura, Gen

AU - Yoshihashi, Hiroshi

PY - 2017

Y1 - 2017

N2 - Geroderma osteodysplastica (GO) is a subtype of cutis laxa syndrome characterized by congenital wrinkly skin, a prematurely aged face, extremely short stature, and osteoporosis leading to recurrent fractures. GO exhibits an autosomal recessive inheritance pattern and is caused by loss-of-function mutations in GORAB, which encodes a protein important for Golgi-related transport. Using whole exome sequencing, we identified novel compound heterozygous nonsense mutations in the GORAB in a GO patient.The patient was a 14-year-old Japanese boy. Wrinkled skin and joint laxity were present at birth. At 1 year of age, he was clinically diagnosed with cutis laxa syndrome based on recurrent long bone fractures and clinical features, including wrinkled skin, joint laxity, and a distinctive face. He did not show retarded gross motor and cognitive development. At 11 years of age, he was treated with oral bisphosphonate and vitamin D owing to recurrent multiple spontaneous fractures of the vertebral and extremity bones associated with a low bone mineral density (BMD). Bisphosphonate treatment improved his BMD and fracture rate. Whole exome sequencing revealed two novel compound heterozygous nonsense mutations in the GORAB gene (p.Arg60* and p.Gln124*), and the diagnosis of GO was established. GO is a rare connective tissue disorder. Approximately 60 cases have been described to date, and this is the first report of a patient from Japan. Few studies have reported the effects of bisphosphonate treatment in GO patients with recurrent spontaneous fractures. Based on this case study, we hypothesize that oral bisphosphonate and vitamin D are effective and safe treatment options for the management of recurrent fractures in GO patients. It is important to establish a precise diagnosis of GO to prevent recurrent fractures and optimize treatment plans.

AB - Geroderma osteodysplastica (GO) is a subtype of cutis laxa syndrome characterized by congenital wrinkly skin, a prematurely aged face, extremely short stature, and osteoporosis leading to recurrent fractures. GO exhibits an autosomal recessive inheritance pattern and is caused by loss-of-function mutations in GORAB, which encodes a protein important for Golgi-related transport. Using whole exome sequencing, we identified novel compound heterozygous nonsense mutations in the GORAB in a GO patient.The patient was a 14-year-old Japanese boy. Wrinkled skin and joint laxity were present at birth. At 1 year of age, he was clinically diagnosed with cutis laxa syndrome based on recurrent long bone fractures and clinical features, including wrinkled skin, joint laxity, and a distinctive face. He did not show retarded gross motor and cognitive development. At 11 years of age, he was treated with oral bisphosphonate and vitamin D owing to recurrent multiple spontaneous fractures of the vertebral and extremity bones associated with a low bone mineral density (BMD). Bisphosphonate treatment improved his BMD and fracture rate. Whole exome sequencing revealed two novel compound heterozygous nonsense mutations in the GORAB gene (p.Arg60* and p.Gln124*), and the diagnosis of GO was established. GO is a rare connective tissue disorder. Approximately 60 cases have been described to date, and this is the first report of a patient from Japan. Few studies have reported the effects of bisphosphonate treatment in GO patients with recurrent spontaneous fractures. Based on this case study, we hypothesize that oral bisphosphonate and vitamin D are effective and safe treatment options for the management of recurrent fractures in GO patients. It is important to establish a precise diagnosis of GO to prevent recurrent fractures and optimize treatment plans.

KW - Bisphosphonate

KW - Cutis laxa syndrome

KW - Geroderma osteodysplastica

KW - Osteoporosis

KW - Whole exome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85027404488&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027404488&partnerID=8YFLogxK

U2 - 10.1016/j.ejmg.2017.08.002

DO - 10.1016/j.ejmg.2017.08.002

M3 - Article

JO - European Journal of Medical Genetics

JF - European Journal of Medical Genetics

SN - 1769-7212

ER -