WDR34, a candidate gene for non-syndromic rod-cone dystrophy

Rod-cone dystrophy (RCD), also called retinitis pigmentosa, is characterized by rod followed by cone photoreceptor degeneration, leading to gradual visual loss. Mutations in over 65 genes have been associated with non-syndromic RCD explaining 60% to 70% of cases, with novel gene defects possibly accounting for the unsolved cases. Homozygosity mapping and whole-exome sequencing applied to a case of autosomal recessive non-syndromic RCD from a consanguineous union identified a homozygous variant in WDR34. Mutations in WDR34 have been previously associated with severe ciliopathy syndromes possibly associated with a retinal dystrophy. This is the first report of a homozygous mutation in WDR34 associated with non-syndromic RCD.Doctoral funding from the Ministère de l'Enseignement Supérieur et de la Recherche; Europe exchange 2018 Erasmus; European Reintegration Grant, Grant/Award Number: PERG04-GA-2008-231125; Fondation de France-Berthe Fouassier; Foundation Fighting Blindness, Grant/Award Number: Grant # CD-CL-0808-0466-CHNO CIC503 recogn; Foundation Voir et Entendre; French Agence Nationale de la Recherche, Grant/Award Numbers: IHU FOReSIGHT: ANR-18-IAHU-0001, LIFESENSES: ANR-10-LABX-65; National Eye Institute [R01EY012910 (EAP), R01EY026904 (KMB/EAP) and P30EY014104 (MEEI core support)], the Foundation Fightin

Linkage analysis of markers on chromosome 11q13 with asthma and atopy in a United Kingdom population

Previous studies have suggested that atopy is linked to the beta chain of the high affinity IgE receptor (Fcvarepsilon R1-beta ) on chromosome 11q13. Fcvarepsilon R1-beta polymorphisms, I181L, V183L, and E237G, are reported to be associated with asthma and atopy. The aim of this study was to investigate linkage to Fcvarepsilon R1-beta in a UK population and to assess the frequency of the polymorphisms and their association with asthma and atopy. A sample of 131 families was recruited at random with a sample of 109 families ascertained via an asthmatic proband. Each subject completed a written and video-assisted questionnaire and underwent bronchial challenge and skin prick testing. Serum total and specific IgE levels were measured. Quantitative scores were derived for asthma and atopy using principal component analysis. Four microsatellite markers were genotyped, including Fcvarepsilon R1-beta . The frequency of the I181L and V183L polymorphisms were determined by sequencing, and the E237G polymorphism was determined using the amplification refractory mutation system. We found no evidence for linkage to Fcvarepsilon R1-beta and only weak evidence for linkage to the less informative marker E237G. We found no examples of the I181L/V183L polymorphism in our population sample. Our study has failed to strengthen the evidence for a candidate gene on chromosome 11q13

Biological networks and GWAS: comparing and combining network methods to understand the genetics of familial breast cancer susceptibility in the GENESIS study

International audienceNetwork approaches to disease use biological networks, which model functional relationships between the molecules in a cell, to generate hypotheses about the genetics of complex diseases. Several among them jointly consider gene scores, representing the association between each gene and the disease, and the biological context of each gene, modeled by a network. Here, we study six such network methods using gene scores from GENESIS, a genome-wide association study (GWAS) on French women with non-BRCA familial breast cancer. We provide a critical comparison of these six methods, discussing the impact of their mathematical formulation and parameters. Using a biological network yields more compelling results than standard GWAS analyses. Indeed, we find significant overlaps between our solutions and the genes identified in the largest GWAS on breast cancer susceptibility. We further propose to combine these solutions into a consensus network, which brings further insights. The consensus network contains COPS5 , a gene related to multiple hallmarks of cancer, and 14 of its neighbors. The main drawback of network methods is that they are not robust to small perturbations in their inputs. Therefore, we propose a stable consensus solution, formed by the most consistently selected genes in multiple subsamples of the data. In GENESIS, it is composed of 68 genes, enriched in known breast cancer susceptibility genes ( BLM, CASP8, CASP10, DNAJC1, FGFR2, MRPS30 , and SLC4A7 , P-value = 3 × 10 4 ) and occupying more central positions in the network than most genes. The network is organized around CUL3 , which is involved in the regulation of several genes linked to cancer progression. In conclusion, we showed how network methods help overcome the lack of statistical power of GWAS and improve their interpretation. Project-agnostic implementations of all methods are available at https://github.com/hclimente/gwas-tools

A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family

Purpose: To identify the genetic defect of a consanguineous Portuguese family with rod-cone dystrophy and varying degrees of decreased audition. Methods: A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive rod-cone dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing. Results: The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe rod-cone dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment. Conclusions: We report a novel truncating mutation in DFNB31 associated with severe rod-cone dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2. © 2011 Molecular Vision.The project was financially supported by the Foundation Fighting Blindness (I.A. FFB Grant N°: CD-CL-0808–0466-CHNO and the CIC503 recognized as an FFB center, FFB Grant No: C-CMM-0907–0428-INSERM04), Agence Nationale de la Recherche (S.S.B.), Foundation Voir et Entendre (C.Z.), Ville de Paris and region Ile de France.Peer Reviewe

Allelic association under map error and recombinational heterogeneity: A tale of two sites

Recombination acts on the genetic map, not on the physical map. On the other hand, the physical map is usually more accurate. Choice of the genetic or physical map for positional cloning by allelic association depends on the goodness of fit of data to each map under an established model. Huntington disease illustrates the usual case in which the greater reliability of physical data outweighs recombinational heterogeneity. Hemochromatosis represents an exceptional case in which unrecognized recombinational heterogeneity retarded positional cloning for a decade. The Malecot model performs well for major genes, but no approach assuming either equilibrium or disequilibrium has been validated for oligogenes contributing to common disease. In this case of greatest interest, the power of allelic association relative to linkage is less clear than for major genes

Boosting GWAS using biological networks: A study on susceptibility to familial breast cancer.

Genome-wide association studies (GWAS) explore the genetic causes of complex diseases. However, classical approaches ignore the biological context of the genetic variants and genes under study. To address this shortcoming, one can use biological networks, which model functional relationships, to search for functionally related susceptibility loci. Many such network methods exist, each arising from different mathematical frameworks, pre-processing steps, and assumptions about the network properties of the susceptibility mechanism. Unsurprisingly, this results in disparate solutions. To explore how to exploit these heterogeneous approaches, we selected six network methods and applied them to GENESIS, a nationwide French study on familial breast cancer. First, we verified that network methods recovered more interpretable results than a standard GWAS. We addressed the heterogeneity of their solutions by studying their overlap, computing what we called the consensus. The key gene in this consensus solution was COPS5, a gene related to multiple cancer hallmarks. Another issue we observed was that network methods were unstable, selecting very different genes on different subsamples of GENESIS. Therefore, we proposed a stable consensus solution formed by the 68 genes most consistently selected across multiple subsamples. This solution was also enriched in genes known to be associated with breast cancer susceptibility (BLM, CASP8, CASP10, DNAJC1, FGFR2, MRPS30, and SLC4A7, P-value = 3 × 10-4). The most connected gene was CUL3, a regulator of several genes linked to cancer progression. Lastly, we evaluated the biases of each method and the impact of their parameters on the outcome. In general, network methods preferred highly connected genes, even after random rewirings that stripped the connections of any biological meaning. In conclusion, we present the advantages of network-guided GWAS, characterize their shortcomings, and provide strategies to address them. To compute the consensus networks, implementations of all six methods are available at https://github.com/hclimente/gwas-tools

A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family.

International audiencePURPOSE:To identify the genetic defect of a consanguineous Portuguese family with rod-cone dystrophy and varying degrees of decreased audition.METHODS:A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive rod-cone dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing.RESULTS:The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe rod-cone dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment.CONCLUSIONS:We report a novel truncating mutation in DFNB31 associated with severe rod-cone dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2

Investigation of DNA repair-related SNPs underlying susceptibility to papillary thyroid carcinoma reveals MGMT as a novel candidate gene in Belarusian children exposed to radiation

BACKGROUND: Genetic factors may influence an individual's sensitivity to ionising radiation and therefore modify his/her risk of developing papillary thyroid carcinoma (PTC). Previously, we reported that common single nucleotide polymorphisms (SNPs) within the DNA damage recognition gene ATM contribute to PTC risk in Belarusian children exposed to fallout from the Chernobyl power plant accident. Here we explored in the same population the contribution of a panel of DNA repair-related SNPs in genes acting downstream of ATM. METHODS: The association of 141 SNPs located in 43 DNA repair genes was examined in 75 PTC cases and 254 controls from the Gomel region in Belarus. All subjects were younger than 15 years at the time of the Chernobyl accident. Conditional logistic regressions accounting for radiation dose were performed with PLINK using the additive allelic inheritance model, and a linkage disequilibrium (LD)-based Bonferroni correction was used for correction for multiple testing. RESULTS: The intronic SNP rs2296675 in MGMT was associated with an increased PTC risk [per minor allele odds ratio (OR) 2.54 95% CI 1.50, 4.30, P per allele = 0.0006, P corr.= 0.05], and gene-wide association testing highlighted a possible role for ERCC5 (P Gene = 0.01) and PCNA (P Gene = 0.05) in addition to MGMT (P Gene = 0.008). CONCLUSIONS: These findings indicate that several genes acting in distinct DNA repair mechanisms contribute to PTC risk. Further investigation is needed to decipher the functional properties of the methyltransferase encoded by MGMT and to understand how alteration of such functions may lead to the development of the most common type of thyroid cancer