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Identification of FAT3 as a new candidate gene for adolescent idiopathic scoliosis

In an effort to identify rare alleles associated with adolescent idiopathic scoliosis (AIS) whole-exome sequencing was performed on a discovery cohort of 73 unrelated patients and 70 age-and sex matched controls, all of French-Canadian ancestry. A collapsing gene burden test was performed to analyze...

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Autores principales: Nada, Dina, Julien, Cédric, Papillon-Cavanagh, Simon, Majewski, Jacek, Elbakry, Mohamed, Elremaly, Wesam, Samuels, Mark E., Moreau, Alain
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296578/
https://www.ncbi.nlm.nih.gov/pubmed/35853984
http://dx.doi.org/10.1038/s41598-022-16620-6
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author Nada, Dina
Julien, Cédric
Papillon-Cavanagh, Simon
Majewski, Jacek
Elbakry, Mohamed
Elremaly, Wesam
Samuels, Mark E.
Moreau, Alain
author_facet Nada, Dina
Julien, Cédric
Papillon-Cavanagh, Simon
Majewski, Jacek
Elbakry, Mohamed
Elremaly, Wesam
Samuels, Mark E.
Moreau, Alain
author_sort Nada, Dina
collection PubMed
description In an effort to identify rare alleles associated with adolescent idiopathic scoliosis (AIS) whole-exome sequencing was performed on a discovery cohort of 73 unrelated patients and 70 age-and sex matched controls, all of French-Canadian ancestry. A collapsing gene burden test was performed to analyze rare protein-altering variants using case–control statistics. Since no single gene achieved statistical significance, targeted exon sequencing was performed for 24 genes with the smallest p values, in an independent replication cohort of unrelated severely affected females with AIS and sex-matched controls (N = 96 each). An excess of rare, potentially protein-altering variants was noted in one particular gene, FAT3, although it did not achieve statistical significance. Independently, we sequenced the exomes of all members of a rare multiplex family of three affected sisters and unaffected parents. All three sisters were compound heterozygous for two rare protein-altering variants in FAT3. The parents were single heterozygotes for each variant. The two variants in the family were also present in our discovery cohort. A second validation step was done, using another independent replication cohort of 258 unrelated AIS patients having reach their skeletal maturity and 143 healthy controls to genotype nine FAT3 gene variants, including the two variants previously identified in the multiplex family: p.L517S (rs139595720) and p.L4544F (rs187159256). Interestingly, two FAT3 variants, rs139595720 (genotype A/G) and rs80293525 (genotype C/T), were enriched in severe scoliosis cases (4.5% and 2.7% respectively) compared to milder cases (1.4% and 0.7%) and healthy controls (1.6% and 0.8%). Our results implicate FAT3 as a new candidate gene in the etiology of AIS.
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spelling pubmed-92965782022-07-21 Identification of FAT3 as a new candidate gene for adolescent idiopathic scoliosis Nada, Dina Julien, Cédric Papillon-Cavanagh, Simon Majewski, Jacek Elbakry, Mohamed Elremaly, Wesam Samuels, Mark E. Moreau, Alain Sci Rep Article In an effort to identify rare alleles associated with adolescent idiopathic scoliosis (AIS) whole-exome sequencing was performed on a discovery cohort of 73 unrelated patients and 70 age-and sex matched controls, all of French-Canadian ancestry. A collapsing gene burden test was performed to analyze rare protein-altering variants using case–control statistics. Since no single gene achieved statistical significance, targeted exon sequencing was performed for 24 genes with the smallest p values, in an independent replication cohort of unrelated severely affected females with AIS and sex-matched controls (N = 96 each). An excess of rare, potentially protein-altering variants was noted in one particular gene, FAT3, although it did not achieve statistical significance. Independently, we sequenced the exomes of all members of a rare multiplex family of three affected sisters and unaffected parents. All three sisters were compound heterozygous for two rare protein-altering variants in FAT3. The parents were single heterozygotes for each variant. The two variants in the family were also present in our discovery cohort. A second validation step was done, using another independent replication cohort of 258 unrelated AIS patients having reach their skeletal maturity and 143 healthy controls to genotype nine FAT3 gene variants, including the two variants previously identified in the multiplex family: p.L517S (rs139595720) and p.L4544F (rs187159256). Interestingly, two FAT3 variants, rs139595720 (genotype A/G) and rs80293525 (genotype C/T), were enriched in severe scoliosis cases (4.5% and 2.7% respectively) compared to milder cases (1.4% and 0.7%) and healthy controls (1.6% and 0.8%). Our results implicate FAT3 as a new candidate gene in the etiology of AIS. Nature Publishing Group UK 2022-07-19 /pmc/articles/PMC9296578/ /pubmed/35853984 http://dx.doi.org/10.1038/s41598-022-16620-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Nada, Dina
Julien, Cédric
Papillon-Cavanagh, Simon
Majewski, Jacek
Elbakry, Mohamed
Elremaly, Wesam
Samuels, Mark E.
Moreau, Alain
Identification of FAT3 as a new candidate gene for adolescent idiopathic scoliosis
title Identification of FAT3 as a new candidate gene for adolescent idiopathic scoliosis
title_full Identification of FAT3 as a new candidate gene for adolescent idiopathic scoliosis
title_fullStr Identification of FAT3 as a new candidate gene for adolescent idiopathic scoliosis
title_full_unstemmed Identification of FAT3 as a new candidate gene for adolescent idiopathic scoliosis
title_short Identification of FAT3 as a new candidate gene for adolescent idiopathic scoliosis
title_sort identification of fat3 as a new candidate gene for adolescent idiopathic scoliosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296578/
https://www.ncbi.nlm.nih.gov/pubmed/35853984
http://dx.doi.org/10.1038/s41598-022-16620-6
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