title: Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta.
abstract: BACKGROUND
  Osteogenesis imperfecta (OI) is a heterogeneous bone disorder characterized by recurrent fractures. Although most cases of OI have heterozygous mutations inCOL1A1orCOL1A2and show autosomal dominant inheritance, during the last years there has been an explosion in the number of genes responsible for both recessive and dominant forms of this condition. Herein, we have analyzed a cohort of patients with OI, all offspring of unaffected parents, to determine the spectrum of variants accounting for these cases. Twenty patients had nonrelated parents and were sporadic, and 21 were born to consanguineous relationships.
  
  
  METHODS
  Mutation analysis was performed using a next-generation sequencing gene panel, homozygosity mapping, and whole exome sequencing (WES).
  
  
  RESULTS
  Patients offspring of nonconsanguineous parents were mostly identified withCOL1A1orCOL1A2heterozygous changes, although there were also a few cases withIFITM5andWNT1heterozygous mutations. Only one sporadic patient was a compound heterozygote for two recessive mutations. Patients offspring of consanguineous parents showed homozygous changes in a variety of genes includingCRTAP,FKBP10,LEPRE1,PLOD2,PPIB,SERPINF1,TMEM38B, andWNT1. In addition, two patients born to consanguineous parents were found to have de novoCOL1A1heterozygous mutations demonstrating that causative variants in the collagen I structural genes cannot be overlooked in affected children from consanguineous couples. Further to this, WES analysis in probands lacking mutations in OI genes revealed deleterious variants inSCN9A,NTRK1, andSLC2A2, which are associated with congenital indifference to pain (CIP) and Fanconi-Bickel syndrome (FBS).
  
  
  CONCLUSIONS
  This work provides useful information for clinical and genetic diagnosis of OI patients with no positive family history of this disease. Our data also indicate that CIP and FBS are conditions to be considered in the differential diagnosis of OI and suggest a positive role ofSCN9AandNTRK1in bone development.
authors.affiliation: Instituto de Investigaciones BiomédicasConsejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridMadridSpain; CIBER de enfermedades Raras (CIBERER)MadridSpain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Caparros-Martin
authors.affiliation: Human Genetics and Genome Research Division Centre of Excellence of Human Genetics National Research Centre Cairo Egypt.
authors.forename: Mona S
authors.initials: MS
authors.lastname: Aglan
authors.affiliation: Human Genetics and Genome Research Division Centre of Excellence of Human Genetics National Research Centre Cairo Egypt.
authors.forename: Samia
authors.initials: S
authors.lastname: Temtamy
authors.affiliation: Human Genetics and Genome Research Division Centre of Excellence of Human Genetics National Research Centre Cairo Egypt.
authors.forename: Ghada A
authors.initials: GA
authors.lastname: Otaify
authors.affiliation: CIBER de enfermedades Raras (CIBERER) Madrid Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Valencia
authors.affiliation: Instituto de Genética Médica y Molecular (INGEMM) Hospital Universitario La Paz-IdiPaz Universidad Autónoma de Madrid Madrid Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Nevado
authors.affiliation: Instituto de Genética Médica y Molecular (INGEMM) Hospital Universitario La Paz-IdiPaz Universidad Autónoma de Madrid Madrid Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Vallespin
authors.affiliation: Instituto de Genética Médica y Molecular (INGEMM) Hospital Universitario La Paz-IdiPaz Universidad Autónoma de Madrid Madrid Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Del Pozo
authors.affiliation: Instituto de Genética Médica y Molecular (INGEMM) Hospital Universitario La Paz-IdiPaz Universidad Autónoma de Madrid Madrid Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Prior de Castro
authors.affiliation: Instituto de Investigaciones BiomédicasConsejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridMadridSpain; CIBER de enfermedades Raras (CIBERER)MadridSpain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Calatrava-Ferreras
authors.affiliation: Orthopedic Surgery Department and Endocrinology Department Hospital Universitario de Getafe Madrid Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Gutierrez
authors.affiliation: Orthopedic Surgery Department and Endocrinology Department Hospital Universitario de Getafe Madrid Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Bueno
authors.affiliation: Orthopedic Surgery Department and Endocrinology Department Hospital Universitario de Getafe Madrid Spain.
authors.forename: Belen
authors.initials: B
authors.lastname: Sagastizabal
authors.affiliation: CIBER de enfermedades Raras (CIBERER)MadridSpain; Unidad de Genética MédicaServicio de PediatríaHospital Universitario Virgen de la ArrixacaMurciaSpain.
authors.forename: Encarna
authors.initials: E
authors.lastname: Guillen-Navarro
authors.affiliation: Unidad de Genética Médica Servicio de Pediatría Hospital Universitario Virgen de la Arrixaca Murcia Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Ballesta-Martinez
authors.affiliation: Unidad de Genética Médica Servicio de Pediatría Hospital Universitario Virgen de la Arrixaca Murcia Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gonzalez
authors.affiliation: Department of Medical Genetics Faculty of Medicine Istanbul Medeniyet University Istanbul Turkey.
authors.forename: Sarenur Y
authors.initials: SY
authors.lastname: Basaran
authors.affiliation: Department of Genetics Faculty of Medicine Erciyes University Kayseri Turkey.
authors.forename: Ruksan
authors.initials: R
authors.lastname: Buyukoglan
authors.affiliation: Department of Genetics School of Medicine Pamukkale University Denizli Turkey.
authors.forename: Bilge
authors.initials: B
authors.lastname: Sarikepe
authors.affiliation: Hospital Universitario Católico Cuenca Ecuador.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Espinoza-Valdez
authors.affiliation: Unidad de Genética Médica Departamento de Pediatría Universidad de Los Andes Mérida Venezuela.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cammarata-Scalisi
authors.affiliation: CIBER de enfermedades Raras (CIBERER)MadridSpain; Instituto de Genética Médica y Molecular (INGEMM)Hospital Universitario La Paz-IdiPazUniversidad Autónoma de MadridMadridSpain.
authors.forename: Victor
authors.initials: V
authors.lastname: Martinez-Glez
authors.affiliation: CIBER de enfermedades Raras (CIBERER)MadridSpain; Instituto de Genética Médica y Molecular (INGEMM)Hospital Universitario La Paz-IdiPazUniversidad Autónoma de MadridMadridSpain; Skeletal Dysplasia Multidisciplinary Unit (UMDE)Hospital Universitario La PazMadridSpain.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
authors.affiliation: CIBER de enfermedades Raras (CIBERER)MadridSpain; Instituto de Genética Médica y Molecular (INGEMM)Hospital Universitario La Paz-IdiPazUniversidad Autónoma de MadridMadridSpain; Skeletal Dysplasia Multidisciplinary Unit (UMDE)Hospital Universitario La PazMadridSpain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.affiliation: Instituto de Investigaciones BiomédicasConsejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridMadridSpain; CIBER de enfermedades Raras (CIBERER)MadridSpain; Skeletal Dysplasia Multidisciplinary Unit (UMDE)Hospital Universitario La PazMadridSpain.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Ruiz-Perez
keywords: Bone development; Fanconi–Bickel syndrome; congenital indifference to pain; osteogenesis imperfecta