Organization and Running of the First Comprehensive Hereditary Cancer Clinic in India

Hereditary cancers are thought to account for around 5% of cancers, particularly breast/ovarian and colorectal cancers. In India there is a paucity of data on hereditary cancers and the mutations in some of the common genes linked to hereditary cancers, such as BRCA1, BRCA2, hMSH2 and hMLH1. The country's first comprehensive hereditary cancer clinic was established in February 2002. The article describes the organization and running of the Clinic. It also discusses some of the social issues relevant to the given population in running the Hereditary Cancer Clinic

Family-based Genome-wide Association Study of South Indian Pedigrees Supports WNT7B as a Central Corneal Thickness Locus

Purpose To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. Methods: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. Results: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval [CI]: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. Conclusions: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits

Multiple Pathway-Based Genetic Variations Associated with Tobacco Related Multiple Primary Neoplasms

BACKGROUND: In order to elucidate a combination of genetic alterations that drive tobacco carcinogenesis we have explored a unique model system and analytical method for an unbiased qualitative and quantitative assessment of gene-gene and gene-environment interactions. The objective of this case control study was to assess genetic predisposition in a biologically enriched clinical model system of tobacco related cancers (TRC), occurring as Multiple Primary Neoplasms (MPN). METHODS: Genotyping of 21 candidate Single Nucleotide Polymorphisms (SNP) from major metabolic pathways was performed in a cohort of 151 MPN cases and 210 cancer-free controls. Statistical analysis using logistic regression and Multifactor Dimensionality Reduction (MDR) analysis was performed for studying higher order interactions among various SNPs and tobacco habit. RESULTS: Increased risk association was observed for patients with at least one TRC in the upper aero digestive tract (UADT) for variations in SULT1A1 Arg²¹³His, mEH Tyr¹¹³His, hOGG1 Ser³²⁶Cys, XRCC1 Arg²⁸⁰His and BRCA2 Asn³⁷²His. Gene-environment interactions were assessed using MDR analysis. The overall best model by MDR was tobacco habit/p53(Arg/Arg)/XRCC1(Arg³⁹⁹His)/mEH(Tyr¹¹³His) that had highest Cross Validation Consistency (8.3) and test accuracy (0.69). This model also showed significant association using logistic regression analysis. CONCLUSION: This is the first Indian study on a multipathway based approach to study genetic susceptibility to cancer in tobacco associated MPN. This approach could assist in planning additional studies for comprehensive understanding of tobacco carcinogenesis

ABCC5, a Gene That Influences the Anterior Chamber Depth, Is Associated with Primary Angle Closure Glaucoma

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size = -0.045 mm, P = 8.17×10-9). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06-1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45×10-9; 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions

Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families

<div><p>Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP) south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s) in the homozygous block identified mutations in ten families; <i>AIPL1</i> – 3 families, <i>RPE65</i>- 2 families, <i>GUCY2D</i>, <i>CRB1</i>, <i>RDH12</i>, <i>IQCB1</i> and <i>SPATA7</i> in one family each, respectively. Six of the ten (60%) mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in <i>MERTK</i>. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for <i>AIPL1</i>, <i>RPE65</i>, <i>CRB1</i>, <i>RDH12</i> genes were as reported earlier.</p></div

Fundus photographs.

<p>Fig 3a A 10yrs old female with c.824G>A p.(Trp278*) mutation in <i>AIPL1</i> (LCA-5 family) showed normal disc, attenuated vessels, (arrow mark indicates) yellow patches in macula. Fig 3b A 14yrs old male with c.824G>A p.(Trp278*) mutation in <i>AIPL1</i> (LCA-5 family, elder sibling) showed normal disc, attenuated vessels, (arrow mark indicates) black pigments in macula. Fig 3c A 18 yrs old female with c.850+1G>T (r.spl?) mutation in <i>RPE65</i> (LCA-1 family) showed pallor disc, attenuated vessels with scar in the macula, peripheral RPE mottling (marked with arrow) Fig 3d A 28yrs old male with c.1409C>T p.(Pro470Leu) mutation in <i>RPE65</i> (LCA-9 family) showed pallor disc, attenuated vessels, normal macula, with salt and pepper fundus. Arrow mark shows distinct pin head size yellow white dot like spots at the posterior pole. Fig 3e A 14 yrs old female with c.2971G>A p.(Gly991Arg) mutation in <i>CRB1</i> (LCA-2 family) showed coin shaped pigment clumps and greyish atrophic changes seen in the macula, (arrow mark indicates the macula) Fig 3f A 18 yrs old female with c.2971G>A p.(Gly991Arg) mutation in <i>CRB1</i> (LCA-2 family, elder sibling) showed pale disc, attenuated vessels, atrophic macula with nummular pigment clumps and greyish atrophic reflex (arrow mark indicates the macula) Fig 3g A 19yrs old male female with c.2971G>A p.(Gly991Arg) mutation in <i>CRB1</i> (LCA-2 family, eldest sibling) showed coin shaped pigment clumps seen in the background (arrow mark indicates the coin shaped clumps) All the three affected siblings show progressive changes in macula with age for <i>CRB1</i> mutation positive family. Fig 3h, 3i, 3j A 24 yrs old female, a 25 yrs old female and a 32 yrs old female with c.721C>T p.(Gln 241*) mutation in <i>MERTK</i> (arRP1 family) showing mild, milder and marked features of RP, respectively. Progressive changes with age in the macula are observed.</p

Probable effects of splice site mutations using HSF 2.4.1 and Mutation Taster and effects of missense mutations using PolyPhen and SIFT.

<p>NA-not applicable</p><p>The human splice finder presents consensous value (CV) which indicate strength of the splice site range from 0 to 100. The splice sites of CV higher than 80 are considered as strong splice sites, 70–80 as less strong and 65–70 as weak, and a CV below 70 is considered to be non-functional [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131679#pone.0131679.ref041" target="_blank">41</a>]. The mutation taster (MT) scores the wild type and the mutant and a confidence score of >0.3 for the mutant indicates gain of completely new splice site [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131679#pone.0131679.ref043" target="_blank">43</a>].</p><p>Probable effects of splice site mutations using HSF 2.4.1 and Mutation Taster and effects of missense mutations using PolyPhen and SIFT.</p

Total number of homozygous blocks ≥ 1Mb in the LCA and arRP families.

<p>Total number of homozygous blocks ≥ 1Mb in the LCA and arRP families.</p

Segregation analysis.

<p>1a:arRP1 <i>MERTK</i> c.721C>T, 1b:LCA-1 <i>RPE65</i> c.850+1G>T, 1c: LCA-2 <i>CRB1</i> c.3307G>A, 1d:LCA-3 <i>GUCY2D</i> c.994delC, 1e:LCA-4 <i>IQCB1</i> c.1278+6T>A, 1f:LCA-5 <i>AIPL1</i> c.824G>A, 1g: LCA-7 <i>RDH12</i> c.344-8C>T, 1h:LCA-8 <i>AIPL1</i> c.247G>A, 1i:LCA-9 <i>RPE65</i> c.1409C>T, 1j:LCA-10 <i>AIPL1</i> c.613_622 delATCATCTGCC, 1k:LCA-11 <i>SPATA7</i> c.913-2A>G. The arrow indicates the index case. The filled in circles and squares are affected females and males respectively. [M];[M]–affected with homozygous mutation, [M]; [=] –carries for any given mutation and [=]; [=] –wild type. Lines above the individual indicate availability of genotype.</p