Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association
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Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association. / Hilger, Alina C; Halbritter, Jan; Pennimpede, Tracie; van der Ven, Amelie; Sarma, Georgia; Braun, Daniela A; Porath, Jonathan D; Kohl, Stefan; Hwang, Daw-Yang; Dworschak, Gabriel C; Hermann, Bernhard G; Pavlova, Anna; El-Maarri, Osman; Nöthen, Markus M; Ludwig, Michael; Reutter, Heiko; Hildebrandt, Friedhelm.
In: HUM MUTAT, Vol. 36, No. 12, 12.2015, p. 1150-4.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association
AU - Hilger, Alina C
AU - Halbritter, Jan
AU - Pennimpede, Tracie
AU - van der Ven, Amelie
AU - Sarma, Georgia
AU - Braun, Daniela A
AU - Porath, Jonathan D
AU - Kohl, Stefan
AU - Hwang, Daw-Yang
AU - Dworschak, Gabriel C
AU - Hermann, Bernhard G
AU - Pavlova, Anna
AU - El-Maarri, Osman
AU - Nöthen, Markus M
AU - Ludwig, Michael
AU - Reutter, Heiko
AU - Hildebrandt, Friedhelm
N1 - © 2015 WILEY PERIODICALS, INC.
PY - 2015/12
Y1 - 2015/12
N2 - The VATER/VACTERL association describes the combination of congenital anomalies including vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. As mutations in ciliary genes were observed in diseases related to VATER/VACTERL, we performed targeted resequencing of 25 ciliary candidate genes as well as disease-associated genes (FOXF1, HOXD13, PTEN, ZIC3) in 123 patients with VATER/VACTERL or VATER/VACTERL-like phenotype. We detected no biallelic mutation in any of the 25 ciliary candidate genes; however, identified an identical, probably disease-causing ZIC3 missense mutation (p.Gly17Cys) in four patients and a FOXF1 de novo mutation (p.Gly220Cys) in a further patient. In situ hybridization analyses in mouse embryos between E9.5 and E14.5 revealed Zic3 expression in limb and prevertebral structures, and Foxf1 expression in esophageal, tracheal, vertebral, anal, and genital tubercle tissues, hence VATER/VACTERL organ systems. These data provide strong evidence that mutations in ZIC3 or FOXF1 contribute to VATER/VACTERL.
AB - The VATER/VACTERL association describes the combination of congenital anomalies including vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. As mutations in ciliary genes were observed in diseases related to VATER/VACTERL, we performed targeted resequencing of 25 ciliary candidate genes as well as disease-associated genes (FOXF1, HOXD13, PTEN, ZIC3) in 123 patients with VATER/VACTERL or VATER/VACTERL-like phenotype. We detected no biallelic mutation in any of the 25 ciliary candidate genes; however, identified an identical, probably disease-causing ZIC3 missense mutation (p.Gly17Cys) in four patients and a FOXF1 de novo mutation (p.Gly220Cys) in a further patient. In situ hybridization analyses in mouse embryos between E9.5 and E14.5 revealed Zic3 expression in limb and prevertebral structures, and Foxf1 expression in esophageal, tracheal, vertebral, anal, and genital tubercle tissues, hence VATER/VACTERL organ systems. These data provide strong evidence that mutations in ZIC3 or FOXF1 contribute to VATER/VACTERL.
KW - Alleles
KW - Anal Canal/abnormalities
KW - Animals
KW - Anus, Imperforate/diagnosis
KW - Cilia/genetics
KW - Computational Biology/methods
KW - DNA Mutational Analysis
KW - Esophagus/abnormalities
KW - Female
KW - Forkhead Transcription Factors/genetics
KW - Genetic Association Studies
KW - Genotype
KW - Heart Defects, Congenital/diagnosis
KW - High-Throughput Nucleotide Sequencing
KW - Homeodomain Proteins/genetics
KW - Humans
KW - Immunohistochemistry
KW - Kidney/abnormalities
KW - Limb Deformities, Congenital/diagnosis
KW - Male
KW - Mice
KW - Mutation
KW - Phenotype
KW - Radius/abnormalities
KW - Spine/abnormalities
KW - Trachea/abnormalities
KW - Transcription Factors/genetics
U2 - 10.1002/humu.22859
DO - 10.1002/humu.22859
M3 - SCORING: Journal article
C2 - 26294094
VL - 36
SP - 1150
EP - 1154
JO - HUM MUTAT
JF - HUM MUTAT
SN - 1059-7794
IS - 12
ER -