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
U2 - 10.1002/ajmg.a.34167
DO - 10.1002/ajmg.a.34167
M3 - Article
C2 - 21834041
AN - SCOPUS:81155160845
SN - 1552-4825
VL - 155
SP - 2170
EP - 2179
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 9
ER -