title: Novel candidate genes putatively involved in stress fracture predisposition detected by whole-exome sequencing.
abstract: While genetic factors in all likelihood contribute to stress fracture (SF) pathogenesis, a few studies focusing on candidate genes have previously been reported. The objective of this study is to gain better understanding on the genetic basis of SF in a gene-naive manner. Exome sequence capture followed by massive parallel sequencing of two pooled DNA samples from Israeli combat soldiers was employed: cases with high grade SF and ethnically matched healthy controls. The resulting sequence variants were individually verified using the Sequenom™ platform and the contribution of the genetic alterations was validated in a second cohort of cases and controls. In the discovery set that included DNA pool of cases (n = 34) and controls (n = 60), a total of 1174 variants with >600 reads/variant/DNA pool were identified, and 146 (in 127 genes) of these exhibited statistically significant (P < 0·05) different rates between SF cases and controls after multiple comparisons correction. Subsequent validation of these 146 sequence variants individually in a total of 136 SF cases and 127 controls using the Sequenom™ platform validated 20/146 variants. Of these, three missense mutations (rs7426114, rs4073918, rs3752135 in the NEB, SLC6A18 and SIGLEC12 genes, respectively) and three synonymous mutations (rs2071856, rs2515941, rs716745 in the ELFN2, GRK4, LRRC55 genes) displayed significant different rates in SF cases compared with controls. Exome sequencing seemingly unravelled novel candidate genes as involved in SF pathogenesis and predisposition.
authors.affiliation: Susanne Levy Gertner Oncogenetics Unit,The Danek Gertner Institute of Human Genetics,Chaim Sheba Medical Center, 52621 Tel-Hashomer,Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.affiliation: Ariel University,Ariel, Samaria,Israel.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Moran
authors.affiliation: Departments of Medicine and Genetics,Albert Einstein College of Medicine,Bronx, NY 10463,USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Ben-Avraham
authors.affiliation: Heller Institute,Sheba Medical Center, 52621 Tel-Hashomer,Israel.
authors.forename: Ran
authors.initials: R
authors.lastname: Yanovich
authors.affiliation: Departments of Medicine and Genetics,Albert Einstein College of Medicine,Bronx, NY 10463,USA.
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000032:analysis*; D016022:Case-Control Studies; D059472:Exome / Q000235:genetics*; D015775:Fractures, Stress / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D015415:Biomarkers