title: Identification of a p.Arg708Gln variant in COL1A2 in atypical femoral fractures.
abstract: OBJECTIVE
  Long-term bisphosphonates exposure is a proven risk factor for atypical femoral fractures (AFF) but several cases occur in untreated patients. The identification of other risk factors for AFF is critical for the management of osteoporosis. We here assessed the genetic factors associated with AFF regardless of the treatment.
  
  
  METHODS
  Cases were identified through ICD-10 codes in 3 academic centers. Medical records were analyzed by 2 investigators that adjudicated X-rays for typical or atypical fractures. Genetic screening for ALPL, SOX9, COL1A1 and COL1A2 variants was performed after patient's information and consent.
  
  
  RESULTS
  A total of 389 cases were identified and 268 were ruled out according to the ASBMR Task Force recommendations. On the remaining 121, 14 (11.6%) were AFF. Anti-osteoporotic drugs were more frequent in the AFF group compared to the typical fracture group (35% vs 5%, P<0.001) but only 4 (28.6%) patients with AFF had been exposed to bisphosphonates. Genetic analysis performed in 5 patients found one with a heterozygous mutation in COL1A2 (rs72658163, NM_000089.3:c.2123G>A, p.Arg708Gln). This rare variant (Minor Allele Frequency=0.0008) causes a missense mutation that alters collagen fibrillogenesis. Eight heterozygous polymorphisms for ALPL were also found in 3 patients.
  
  
  CONCLUSIONS
  Genetic screening for variants in only 4 genes and 5 patients with AFF resulted in the identification of genetic variants in 3 patients including a rare variant in COL1A2, suggesting a possible genetic susceptibility to AFF. This finding should encourage clinician to further genotype patients with AFF in a collaborative multicentric project.
authors.affiliation: Inserm UMR1132, université Paris Diderot, Sorbonne Paris Cité, 2, rue Ambroise-Paré, 75010 Paris, France; Department of rheumatology, Lariboisière hospital, université Paris Diderot, 75010 Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Funck-Brentano
authors.affiliation: Inserm UMR1132, université Paris Diderot, Sorbonne Paris Cité, 2, rue Ambroise-Paré, 75010 Paris, France.
authors.forename: Agnes
authors.initials: A
authors.lastname: Ostertag
authors.affiliation: Department of rheumatology, Poitiers university hospital, 86021 Poitiers, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Debiais
authors.affiliation: Department of rheumatology, Amiens university hospital, 8000 Amiens, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Fardellone
authors.affiliation: Inserm UMR1132, université Paris Diderot, Sorbonne Paris Cité, 2, rue Ambroise-Paré, 75010 Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Collet
authors.affiliation: Unité de génétique constitutionnelle, centre hospitalier de Versailles, 78150 Le Chesnay, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Mornet
authors.affiliation: Inserm UMR1132, université Paris Diderot, Sorbonne Paris Cité, 2, rue Ambroise-Paré, 75010 Paris, France; Department of rheumatology, Lariboisière hospital, université Paris Diderot, 75010 Paris, France. Electronic address: martine.cohen-solal@inserm.fr.
authors.forename: Martine
authors.initials: M
authors.lastname: Cohen-Solal
mesh_terms: D000046:Academic Medical Centers; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000235:genetics*; D024042:Collagen Type I / Q000235:genetics*; D016208:Databases, Factual; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics*; D005500:Follow-Up Studies; D005602:France; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D014644:Genetic Variation; D006620:Hip Fractures / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D058866:Osteoporotic Fractures / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics*; D011379:Prognosis; D011859:Radiography / Q000379:methods; D012189:Retrospective Studies; D018570:Risk Assessment
chemical_list: C000601279:COL1A2 protein, human; D024042:Collagen Type I; C548267:ALPL protein, human; D000469:Alkaline Phosphatase
keywords: ALPL; Atypical femoral fractures; Bisphosphonates; COL1A2; Genetic variants