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Genetics Research Genetics Research

Article contents

Novel candidate genes putatively involved in stress fracture predisposition detected by whole-exome sequencing

Published online by Cambridge University Press:  28 May 2014

EITAN FRIEDMAN ,
DANIEL S. MORAN ,
DANNY BEN-AVRAHAM ,
RAN YANOVICH  and
GIL ATZMON
EITAN FRIEDMAN*
Affiliation:
Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Tel-Hashomer, Israel The Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel
DANIEL S. MORAN
Affiliation:
Ariel University, Ariel, Samaria, Israel Heller Institute, Sheba Medical Center, 52621 Tel-Hashomer, Israel
DANNY BEN-AVRAHAM
Affiliation:
Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10463, USA
RAN YANOVICH
Affiliation:
Heller Institute, Sheba Medical Center, 52621 Tel-Hashomer, Israel
GIL ATZMON
Affiliation:
Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10463, USA
*
* Corresponding author: Head, the Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Tel-Hashomer, Israel. Tel.: 972 3 530 3173. Fax: 972 3 535 7308. E-mail: eitan.friedman@sheba.health.gov.il; eitan211@netvision.net.il
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Summary

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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.

Type
Research Papers
Information
Genetics Research , Volume 96 , 2014 , e004
Copyright
Copyright © Cambridge University Press 2014 

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