Novel mutation in FOXC1 wing region causing Axenfeld-Rieger anomaly

Purpose: To determine the possible molecular genetic defect underlying Axenfeld-Rieger anomaly (ARA) and to identify the pathogenic mutation causing this anterior segment dysgenesis in an Indian pedigree. Methods: The FOXC1 gene was amplified from genomic DNA of members of an ARA-affected family and control subjects using four novel sets of primers. The amplicons were directly sequenced, and the sequences were analyzed to identify the disease-causing mutation. Results: A heterozygous novel missense mutation was identified in the coding region of the FOXC1 gene in all three patients in this family. Consistent with the autosomal dominant inheritance pattern, the mutation segregated with the disease phenotype and was fully penetrant. The mutation was found in the wing region of the highly conserved forkhead domain of the FOXC1 gene and resulted in a very severe phenotype leading to blindness. Conclusions: This is the first study to demonstrate that a mutation in the FOXC1 wing region can cause an anterior segment dysgenesis of the eye. This mutation resulted in blindness in the ARA-affected family, and the findings suggest that the FOXC1 wing region has a functional role in the normal development of the eye. Moreover, this is the first study from India to report the genetic etiology of Axenfeld-Rieger anomaly. Genotype-phenotype correlations of FOXC1 may help in establishing the disease prognosis and also in understanding the clinical and genetic heterogeneity associated with various anterior segment dysgenesis caused by this gene

HPPD: A newly recognized autosomal dominant disorder involving hypertelorism, preauricular sinus, punctal pits, and deafness mapping to chromosome 14q31

We report on a novel autosomal dominant disorder with variable phenotypic expression in a three-generation family; the major features include hypertelorism, preauricular sinus, deafness, and punctal pits with lacrimal-duct obstruction. We ruled out the involvement of EYA1, SIX1, and SIX5 as candidate genes by direct sequencing of their exons and by SNP-based linkage analysis. Subsequent SNP-based whole-genome genotyping and parametric multipoint linkage analysis gave lod scores >1 at 14q31 (LOD=3.14), 11q25 (LOD=1.87), and 8p23 (LOD=1.18). By genotyping additional microsatellite markers at two of these three loci and using an expanded phenotype definition, the LOD at 14q31 increased to 3.34. Direct sequencing of the gene exons within the 14q31 critical interval and a custom aCGH experiment did not show any pathogenic mutation or copy-number changes. Further sequencing of 21kb of promoter regions showed a novel polymorphism 1,249bp upstream from the SELIL start codon that segregated with the disease haplotype. Cloning the novel polymorphism into luciferase reporter constructs resulted in a 20% reduction in the expression levels. The identification of this family with a distinctive clinical phenotype and linkage to a novel locus at 14q31 supports the existence of a new syndrome of the branchial cleft

Neonatal mucolipidosis type II alpha/beta due to compound heterozygosity for a known and novel

We report on a newborn with IUGR, rhizomelic dwarfism, and suspected chondrodysplasia punctata. At birth, OI was suspected; however, a skeletal survey suggested ML II alpha/beta. Sequencing revealed compound heterozygosity for a reported pathogenic and novel but expected pathogeni

Defining the Contribution of <i>CNTNAP2</i> to Autism Susceptibility

<div><p>Multiple lines of genetic evidence suggest a role for <i>CNTNAP2</i> in autism. To assess its population impact we studied 2148 common single nucleotide polymorphisms (SNPs) using transmission disequilibrium test (TDT) across the entire ~3.3 Mb <i>CNTNAP2</i> locus in 186 (408 trios) multiplex and 323 simplex families with autistic spectrum disorder (ASD). This analysis yielded two SNPs with nominal statistical significance (rs17170073, <i>p</i> = 2.0 x 10^-4; rs2215798, <i>p</i> = 1.6 x 10^-4) that did not survive multiple testing. In a combined analysis of all families, two highly correlated (<i>r</i>² = 0.99) SNPs in intron 14 showed significant association with autism (rs2710093, <i>p</i> = 9.0 x 10^-6; rs2253031, <i>p</i> = 2.5 x 10^-5). To validate these findings and associations at SNPs from previous autism studies (rs7794745, rs2710102 and rs17236239) we genotyped 2051 additional families (572 multiplex and 1479 simplex). None of these variants were significantly associated with ASD after corrections for multiple testing. The analysis of Mendelian errors within each family did not indicate any segregating deletions. Nevertheless, a study of <i>CNTNAP2</i> gene expression in brains of autistic patients and of normal controls, demonstrated altered expression in a subset of patients (<i>p</i> = 1.9 x10^-5). Consequently, this study suggests that although <i>CNTNAP2</i> dysregulation plays a role in some cases, its population contribution to autism susceptibility is limited.</p> </div

<i>CNTNAP2</i> expression in autism and control brains.

<p>(A) <i>CNTNAP2</i> expression normalized to <i>TBP</i> and (B) log transformed. (C) <i>CNTNAP2</i> expression as a function of age in cases (red dots) and controls (black dots), and (D) <i>CNTNAP2</i> expression in autism and control brains adjusted for age and age² effects. </p

A plot of -log₁₀<i>p</i> across <i>CNTNAP2</i> from family-based association test (TDT) results on 323 simplex families.

<p>A plot of -log₁₀<i>p</i> across <i>CNTNAP2</i> from family-based association test (TDT) results on 323 simplex families.</p

A plot of -log₁₀<i>p</i> across <i>CNTNAP2</i> from family-based association test (TDT) results on 186 multiplex families.

<p>The physical position within the <i>CNTNAP2</i> locus in megabases (Mb) and the -log₁₀<i>p</i>-values are shown on the x and y-axis, respectively. SNPs with minor allele frequency (MAF) <10% and those with MAF ≥10% are shown as red and blue filled circles, respectively. A horizontal line represents the <i>CNTNAP2</i> gene, with vertical hash marks indicating exons, and locations of individual SNPs showing region-wide statistical significance in prior studies are indicated. The recombination rate in cM/Mb (right y-axis) is shown in orange. The horizontal grey dashed line represents the -log₁₀<i>p</i>-value for region-wide significance level (7.5 x 10^-5).</p