The October 2014 issue of Birth Defects Research Part A: Clinical and Molecular Teratology is available and you may access the table of contents online. Members who subscribe to BDR may access the full articles via the Teratology website using your member login information.
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The acronym VATER/VACTERL association describes the combination of at least three of the following cardinal features: vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. Heiko Reutter et al. performed FGF8 gene analysis in 49 patients with VATER/VACTERL association and 27 patients presenting with a VATER/VACTERL-like phenotype. They identified two heterozygous FGF8 mutations in patients displaying either VATER/VACTERL association (p.Gly29_Arg34dup) or a VATER/VACTERL-like phenotype (p.Pro26Leu) without limb anomalies. These results suggest that FGF8 mutations contribute to the formation of the VATER/VACTERL association. Further studies are needed to support this observation.
The prenatal diagnosis procedure chorionic villus sampling is associated with an increased risk of vascular disruption limb defects. Some studies have suggested that these defects are more common among infants born to women 35 years and older, while other studies have shown a correlation with younger mothers. 106 infants with vascular disruption defects and 67 with preaxial polydactyly were studied by Hanah Z. Nasri et al. The results show that women 35 years old or older did not have increased risk for having a child with vascular disruption defects, but these defects were more common among infants of young (≤19) mothers, compared with the preaxial polydactyly group.
Split-hand/foot malformation (SHFM) is a clinically and genetically heterogeneous limb abnormality characterized by the absence or hypoplasia of the central rays. SHFM1, which is one out of seven known SHFM loci maps to 7q21.2-q21.3. In most cases, SHFM1 results from heterozygous deletions encompassing DLX5/DLX6 genes or from inversions and translocations separating the genes from their limb specific enhancers. In this issue Aleksander Jamsheer et al. report on four male individuals from two unrelated Polish families presenting with isolated SHFM. Sanger sequencing of DLX5revealed a novel heterozygous nonsense mutation c.G115T(p.E39X) in both index patients. This is the first report of a heterozygous DLX5 nonsense mutation resulting in incompletely penetrant autosomal dominant isolated SHFM1.
The heritable multifactorial etiology of human nonsyndromic cleft lip with or without cleft palate (CL ± P) is not understood. In the mouse CL ± P occurs in 15% of neonates in the homozygous A/WySn mouse strain, with a multifactorial genetic etiology, the clf1 and clf2 variant genes. Clf1 acts as a mutant allele of Wnt9b but its coding sequence is normal. An IAP (intracisternal A particle) retrotransposon inserted near the Wnt9b gene is associated with clf1. In this issue, Diana M. Juriloff et al. show that the clf1 mutation in A/WySn is a “metastable epiallele”, in which stochastic deficiency of DNA methylation of a retrotransposon uniquely inserted near the Wnt9b gene allows transcriptional activity of the retrotransposon and interference with transcription from Wnt9b. The authors suggest that methylation of metastable epialleles should be investigated in human nonsyndromic CL ± P.