Rare Novel Genetic Variants of the OFD1 Gene Associated With a Familial Form and a Sporadic Case of Long Bone Atypical Fractures
8 affiliations
- 1CHU de Québec‐Université Laval Research Centre Quebec Quebec Canada
- 2Institut de Biologie intégrative et Des systèmes (IBIS), Université Laval Quebec Quebec Canada
- 3Department of Genetics CHU de Québec‐Université Laval Quebec Quebec Canada
- 4Mc‐Gill University Montréal Quebec Canada
- 5Department of Medicine Université Laval Quebec Quebec Canada
- 6Faculté de médecine Dentaire Université Laval Québec Quebec Canada
- 7Department of Medicine, Faculté de Médecine Université de Montréal Montréal Quebec Canada
- 8Department of Rheumatology CHU de Québec‐Université Laval Quebec Quebec Canada
Abstract
We describe a family with 11 members affected by oral, facial and digital findings, as well as adult‐onset multiple long bone insufficiency fractures mimicking atypical femur fractures (AFF) on radiographs. The analysis of the pedigree of this family suggested an X‐linked dominant inheritance. We performed whole‐exome sequencing in this family. A rare novel variant, p.Ala642Asp (NM_003611, c.1925C>A, hg19) of the OFD1 gene was the only candidate on the X chromosome segregating with the phenotype within the family. The OFD1 gene targeted sequencing was carried out on 49 patients with AFF and 100 healthy controls. We detected another rare variant, p.Lys668Asn (NM_003611, c.2004G>C, hg19) of the OFD1 gene, in a woman with AFF. The structure of OFD1 protein has been predicted by AlphaFold 3 (AF3). According to the AF3 model of OFD1, the destabilization of the dimerization of OFD1 by the p.Ala642Asp variant and the breaking of ionic bond by the p.Lys668Asn variant could be pathogenic. This family demonstrates that such insufficiency fractures of long bones may occur in patients with oral‐facial‐digital syndrome and provides novel insight into the pathophysiology of these fractures and their association with dental and facial hypoplasia.
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BibTeX
@article{boisvert2026rare,
title = {{Rare Novel Genetic Variants of the OFD1 Gene Associated With a Familial Form and a Sporadic Case of Long Bone Atypical Fractures}},
author = {Marie‐Ève Boisvert and Halim Maaroufi and Rachel Laframboise and Frédéric Fournier and Suzanne N. Morin and Edith Gagnon and Claudia Gagnon and Fabrice Mac‐Way and Mahmoud Rouabhia and Louis‐Georges Ste‐Marie and Arnaud Droit and Jacques P. Brown and Laëtitia Michou},
journal = {Clinical Genetics},
year = {2026},
month = aug,
doi = {10.1111/cge.70232},
url = {https://doi.org/10.1111/cge.70232},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Rare Novel Genetic Variants of the OFD1 Gene Associated With a Familial Form and a Sporadic Case of Long Bone Atypical Fractures
AU - Marie‐Ève Boisvert
AU - Halim Maaroufi
AU - Rachel Laframboise
AU - Frédéric Fournier
AU - Suzanne N. Morin
AU - Edith Gagnon
AU - Claudia Gagnon
AU - Fabrice Mac‐Way
AU - Mahmoud Rouabhia
AU - Louis‐Georges Ste‐Marie
AU - Arnaud Droit
AU - Jacques P. Brown
AU - Laëtitia Michou
PY - 2026
DA - 2026/08/23
JO - Clinical Genetics
DO - 10.1111/cge.70232
UR - https://doi.org/10.1111/cge.70232
AB - We describe a family with 11 members affected by oral, facial and digital findings, as well as adult‐onset multiple long bone insufficiency fractures mimicking atypical femur fractures (AFF) on radiographs. The analysis of the pedigree of this family suggested an X‐linked dominant inheritance. We performed whole‐exome sequencing in this family. A rare novel variant, p.Ala642Asp (NM_003611, c.1925C>A, hg19) of the OFD1 gene was the only candidate on the X chromosome segregating with the phenotype within the family. The OFD1 gene targeted sequencing was carried out on 49 patients with AFF and 100 healthy controls. We detected another rare variant, p.Lys668Asn (NM_003611, c.2004G>C, hg19) of the OFD1 gene, in a woman with AFF. The structure of OFD1 protein has been predicted by AlphaFold 3 (AF3). According to the AF3 model of OFD1, the destabilization of the dimerization of OFD1 by the p.Ala642Asp variant and the breaking of ionic bond by the p.Lys668Asn variant could be pathogenic. This family demonstrates that such insufficiency fractures of long bones may occur in patients with oral‐facial‐digital syndrome and provides novel insight into the pathophysiology of these fractures and their association with dental and facial hypoplasia.
SN - 0009-9163
SN - 1399-0004
ER -