Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot

Katelyn S. Weymouth, Susan H. Blanton, Michael J. Bamshad, Anita E. Beck, Christine Alvarez, Steve Richards, Christina A. Gurnett, Matthew B. Dobbs, Douglas Barnes, Laura E. Mitchell, Jacqueline T. Hecht

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Isolated clubfoot is a relatively common birth defect that affects approximately 4,000 newborns in the US each year. Calf muscles in the affected leg(s) are underdeveloped and remain small even after corrective treatment. This observation suggests that variants in genes that influence muscle development are priority candidate risk factors for clubfoot. This contention is further supported by the discovery that mutations in genes that encode components of the muscle contractile complex (MYH3, TPM2, TNNT3, TNNI2, and MYH8) cause congenital contractures, including clubfoot, in distal arthrogryposis (DA) syndromes. Interrogation of 15 genes encoding proteins that control myofiber contractility in a cohort of both non-Hispanic White (NHW) and Hispanic families, identified positive associations (P<0.05) with SNPs in 12 genes; only 1 was identified in a family-based validation dataset. Six SNPs in TNNC2 deviated from Hardy-Weinberg equilibrium in mothers in our NHW discovery dataset. Relative risk and likelihood ratio tests showed evidence for a maternal genotypic effect with TNNC2/rs383112 and an inherited/child genotypic effect with two SNPs, TNNC2/rs4629 and rs383112. Associations with multiple SNPs in TPM1 were identified in the NHW discovery (rs4075583, P=0.01), family-based validation (rs1972041, P=0.000074), and case-control validation (rs12148828, P=0.04) datasets. Gene interactions were identified between multiple muscle contraction genes with many of the interactions involving at least one potential regulatory SNP. Collectively, our results suggest that variation in genes that encode contractile proteins of skeletal myofibers may play a role in the etiology of clubfoot.

Original languageEnglish (US)
Pages (from-to)2170-2179
Number of pages10
JournalAmerican Journal of Medical Genetics, Part A
Volume155
Issue number9
DOIs
StatePublished - Sep 2011

Fingerprint

Clubfoot
Contractile Proteins
Muscle Proteins
Single Nucleotide Polymorphism
Genes
Arthrogryposis
Gene Components
Muscles
Muscle Development
Contracture
Muscle Contraction
Hispanic Americans
Leg
Odds Ratio
Mothers
Newborn Infant
Mutation
Datasets
Proteins

Keywords

  • Association study
  • Clubfoot
  • Contraction
  • Distal arthrogryposis
  • Genetics
  • Muscle

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot. / Weymouth, Katelyn S.; Blanton, Susan H.; Bamshad, Michael J.; Beck, Anita E.; Alvarez, Christine; Richards, Steve; Gurnett, Christina A.; Dobbs, Matthew B.; Barnes, Douglas; Mitchell, Laura E.; Hecht, Jacqueline T.

In: American Journal of Medical Genetics, Part A, Vol. 155, No. 9, 09.2011, p. 2170-2179.

Research output: Contribution to journalArticle

Weymouth, KS, Blanton, SH, Bamshad, MJ, Beck, AE, Alvarez, C, Richards, S, Gurnett, CA, Dobbs, MB, Barnes, D, Mitchell, LE & Hecht, JT 2011, 'Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot', American Journal of Medical Genetics, Part A, vol. 155, no. 9, pp. 2170-2179. https://doi.org/10.1002/ajmg.a.34167
Weymouth, Katelyn S. ; Blanton, Susan H. ; Bamshad, Michael J. ; Beck, Anita E. ; Alvarez, Christine ; Richards, Steve ; Gurnett, Christina A. ; Dobbs, Matthew B. ; Barnes, Douglas ; Mitchell, Laura E. ; Hecht, Jacqueline T. / Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot. In: American Journal of Medical Genetics, Part A. 2011 ; Vol. 155, No. 9. pp. 2170-2179.
@article{dddf0e14365d4fa5ace73282908f0363,
title = "Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot",
abstract = "Isolated clubfoot is a relatively common birth defect that affects approximately 4,000 newborns in the US each year. Calf muscles in the affected leg(s) are underdeveloped and remain small even after corrective treatment. This observation suggests that variants in genes that influence muscle development are priority candidate risk factors for clubfoot. This contention is further supported by the discovery that mutations in genes that encode components of the muscle contractile complex (MYH3, TPM2, TNNT3, TNNI2, and MYH8) cause congenital contractures, including clubfoot, in distal arthrogryposis (DA) syndromes. Interrogation of 15 genes encoding proteins that control myofiber contractility in a cohort of both non-Hispanic White (NHW) and Hispanic families, identified positive associations (P<0.05) with SNPs in 12 genes; only 1 was identified in a family-based validation dataset. Six SNPs in TNNC2 deviated from Hardy-Weinberg equilibrium in mothers in our NHW discovery dataset. Relative risk and likelihood ratio tests showed evidence for a maternal genotypic effect with TNNC2/rs383112 and an inherited/child genotypic effect with two SNPs, TNNC2/rs4629 and rs383112. Associations with multiple SNPs in TPM1 were identified in the NHW discovery (rs4075583, P=0.01), family-based validation (rs1972041, P=0.000074), and case-control validation (rs12148828, P=0.04) datasets. Gene interactions were identified between multiple muscle contraction genes with many of the interactions involving at least one potential regulatory SNP. Collectively, our results suggest that variation in genes that encode contractile proteins of skeletal myofibers may play a role in the etiology of clubfoot.",
keywords = "Association study, Clubfoot, Contraction, Distal arthrogryposis, Genetics, Muscle",
author = "Weymouth, {Katelyn S.} and Blanton, {Susan H.} and Bamshad, {Michael J.} and Beck, {Anita E.} and Christine Alvarez and Steve Richards and Gurnett, {Christina A.} and Dobbs, {Matthew B.} and Douglas Barnes and Mitchell, {Laura E.} and Hecht, {Jacqueline T.}",
year = "2011",
month = "9",
doi = "10.1002/ajmg.a.34167",
language = "English (US)",
volume = "155",
pages = "2170--2179",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
publisher = "Wiley-Liss Inc.",
number = "9",

}

TY - JOUR

T1 - Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot

AU - Weymouth, Katelyn S.

AU - Blanton, Susan H.

AU - Bamshad, Michael J.

AU - Beck, Anita E.

AU - Alvarez, Christine

AU - Richards, Steve

AU - Gurnett, Christina A.

AU - Dobbs, Matthew B.

AU - Barnes, Douglas

AU - Mitchell, Laura E.

AU - Hecht, Jacqueline T.

PY - 2011/9

Y1 - 2011/9

N2 - Isolated clubfoot is a relatively common birth defect that affects approximately 4,000 newborns in the US each year. Calf muscles in the affected leg(s) are underdeveloped and remain small even after corrective treatment. This observation suggests that variants in genes that influence muscle development are priority candidate risk factors for clubfoot. This contention is further supported by the discovery that mutations in genes that encode components of the muscle contractile complex (MYH3, TPM2, TNNT3, TNNI2, and MYH8) cause congenital contractures, including clubfoot, in distal arthrogryposis (DA) syndromes. Interrogation of 15 genes encoding proteins that control myofiber contractility in a cohort of both non-Hispanic White (NHW) and Hispanic families, identified positive associations (P<0.05) with SNPs in 12 genes; only 1 was identified in a family-based validation dataset. Six SNPs in TNNC2 deviated from Hardy-Weinberg equilibrium in mothers in our NHW discovery dataset. Relative risk and likelihood ratio tests showed evidence for a maternal genotypic effect with TNNC2/rs383112 and an inherited/child genotypic effect with two SNPs, TNNC2/rs4629 and rs383112. Associations with multiple SNPs in TPM1 were identified in the NHW discovery (rs4075583, P=0.01), family-based validation (rs1972041, P=0.000074), and case-control validation (rs12148828, P=0.04) datasets. Gene interactions were identified between multiple muscle contraction genes with many of the interactions involving at least one potential regulatory SNP. Collectively, our results suggest that variation in genes that encode contractile proteins of skeletal myofibers may play a role in the etiology of clubfoot.

AB - Isolated clubfoot is a relatively common birth defect that affects approximately 4,000 newborns in the US each year. Calf muscles in the affected leg(s) are underdeveloped and remain small even after corrective treatment. This observation suggests that variants in genes that influence muscle development are priority candidate risk factors for clubfoot. This contention is further supported by the discovery that mutations in genes that encode components of the muscle contractile complex (MYH3, TPM2, TNNT3, TNNI2, and MYH8) cause congenital contractures, including clubfoot, in distal arthrogryposis (DA) syndromes. Interrogation of 15 genes encoding proteins that control myofiber contractility in a cohort of both non-Hispanic White (NHW) and Hispanic families, identified positive associations (P<0.05) with SNPs in 12 genes; only 1 was identified in a family-based validation dataset. Six SNPs in TNNC2 deviated from Hardy-Weinberg equilibrium in mothers in our NHW discovery dataset. Relative risk and likelihood ratio tests showed evidence for a maternal genotypic effect with TNNC2/rs383112 and an inherited/child genotypic effect with two SNPs, TNNC2/rs4629 and rs383112. Associations with multiple SNPs in TPM1 were identified in the NHW discovery (rs4075583, P=0.01), family-based validation (rs1972041, P=0.000074), and case-control validation (rs12148828, P=0.04) datasets. Gene interactions were identified between multiple muscle contraction genes with many of the interactions involving at least one potential regulatory SNP. Collectively, our results suggest that variation in genes that encode contractile proteins of skeletal myofibers may play a role in the etiology of clubfoot.

KW - Association study

KW - Clubfoot

KW - Contraction

KW - Distal arthrogryposis

KW - Genetics

KW - Muscle

UR - http://www.scopus.com/inward/record.url?scp=81155160845&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81155160845&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.34167

DO - 10.1002/ajmg.a.34167

M3 - Article

VL - 155

SP - 2170

EP - 2179

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 9

ER -