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41.
Chandree?L. Beaulieu Jacek Majewski Jeremy Schwartzentruber Mark?E. Samuels Bridget?A. Fernandez Francois?P. Bernier Michael Brudno Bartha Knoppers Janet Marcadier David Dyment Shelin Adam Dennis?E. Bulman Steve?J.M. Jones Denise Avard Minh?Thu Nguyen Francois Rousseau Christian Marshall Richard?F. Wintle Yaoqing Shen Stephen?W. Scherer FORGE Canada Consortium Jan?M. Friedman Jacques?L. Michaud Kym?M. Boycott 《American journal of human genetics》2014,94(6):809-817
Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing. The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers from across Canada. From nation-wide requests for proposals, 264 disorders were selected for study from the 371 submitted; disease-causing variants (including in 67 genes not previously associated with human disease; 41 of these have been genetically or functionally validated, and 26 are currently under study) were identified for 146 disorders over a 2-year period. Here, we present our experience with four strategies employed for gene discovery and discuss FORGE’s impact in a number of realms, from clinical diagnostics to the broadening of the phenotypic spectrum of many diseases to the biological insight gained into both disease states and normal human development. Lastly, on the basis of this experience, we discuss the way forward for rare-disease genetic discovery both in Canada and internationally. 相似文献
42.
Detelina Grozeva Keren Carss Olivera Spasic-Boskovic Michael?J. Parker Hayley Archer Helen?V. Firth Soo-Mi Park Natalie Canham Susan?E. Holder Meredith Wilson Anna Hackett Michael Field James?A.B. Floyd UKK Consortium Matthew Hurles F.?Lucy Raymond 《American journal of human genetics》2014,94(4):618-624
To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations—four nonsense (c.1195A>T [p.Lys399∗], c.1333C>T [p.Arg445∗], c.1866C>G [p.Tyr622∗], and c.3001C>T [p.Arg1001∗]) and three frameshift (c.2177_2178del [p.Thr726Asnfs∗39], c.3771dup [p.Ser1258Glufs∗65], and c.3856del [p.Ser1286Leufs∗84])—were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID. 相似文献
43.
Genetic diversity in Puerto Rico and its implications for the peopling of the Island and the West Indies 下载免费PDF全文
Miguel G. Vilar Carlalynne Melendez Akiva B. Sanders Akshay Walia Jill B. Gaieski Amanda C. Owings Theodore G. Schurr The Genographic Consortium 《American journal of physical anthropology》2014,155(3):352-368
Puerto Rico and the surrounding islands rest on the eastern fringe of the Caribbean's Greater Antilles, located less than 100 miles northwest of the Lesser Antilles. Puerto Ricans are genetic descendants of pre‐Columbian peoples, as well as peoples of European and African descent through 500 years of migration to the island. To infer these patterns of pre‐Columbian and historic peopling of the Caribbean, we characterized genetic diversity in 326 individuals from the southeastern region of Puerto Rico and the island municipality of Vieques. We sequenced the mitochondrial DNA (mtDNA) control region of all of the samples and the complete mitogenomes of 12 of them to infer their putative place of origin. In addition, we genotyped 121 male samples for 25 Y‐chromosome single nucleotide polymorphism and 17 STR loci. Approximately 60% of the participants had indigenous mtDNA haplotypes (mostly from haplogroups A2 and C1), while 25% had African and 15% European haplotypes. Three A2 sublineages were unique to the Greater Antilles, one of which was similar to Mesoamerican types, while C1b haplogroups showed links to South America, suggesting that people reached the island from the two distinct continental source areas. However, none of the male participants had indigenous Y‐chromosomes, with 85% of them instead being European/Mediterranean and 15% sub‐Saharan African in origin. West Eurasian Y‐chromosome short tandem repeat haplotypes were quite diverse and showed similarities to those observed in southern Europe, North Africa and the Middle East. These results attest to the distinct, yet equally complex, pasts for the male and female ancestors of modern day Puerto Ricans. Am J Phys Anthropol 155:352–368, 2014. © 2014 Wiley Periodicals, Inc. 相似文献
44.
Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia
Moreno-De-Luca D;SGENE Consortium Mulle JG;Simons Simplex Collection Genetics Consortium Kaminsky EB Sanders SJ;GeneSTAR Myers SM Adam MP Pakula AT Eisenhauer NJ Uhas K Weik L Guy L Care ME Morel CF Boni C Salbert BA Chandrareddy A Demmer LA Chow EW Surti U Aradhya S Pickering DL Golden DM Sanger WG Aston E Brothman AR Gliem TJ Thorland EC Ackley T Iyer R Huang S Barber JC Crolla JA Warren ST Martin CL Ledbetter DH 《American journal of human genetics》2010,87(5):618-630
Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10−5). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only. 相似文献
45.
Tourette Syndrome Association International Consortium for Genetics 《American journal of human genetics》2007,80(2):265-272
Tourette disorder (TD) is a neuropsychiatric disorder with a complex mode of inheritance and is characterized by multiple waxing and waning motor and phonic tics. This article reports the results of the largest genetic linkage study yet undertaken for TD. The sample analyzed includes 238 nuclear families yielding 304 "independent" sibling pairs and 18 separate multigenerational families, for a total of 2,040 individuals. A whole-genome screen with the use of 390 microsatellite markers was completed. Analyses were completed using two diagnostic classifications: (1) only individuals with TD were included as affected and (2) individuals with either TD or chronic-tic (CT) disorder were included as affected. Strong evidence of linkage was observed for a region on chromosome 2p (-log P = 4.42, P = 3.8 x 10(-5) in the analyses that included individuals with TD or CT disorder as affected. Results in several other regions also provide moderate evidence (-log P >2.0) of additional susceptibility loci for TD. 相似文献
46.
Peter C Bruford M Perez T Dalamitra S Hewitt G Erhardt G;ECONOGENE Consortium 《Animal genetics》2007,38(1):37-44
The population structure and genetic diversity of 57 European and Middle Eastern marginal and cosmopolitan sheep breeds from 15 countries were analysed by typing 31 microsatellite markers. Mean unbiased expected heterozygosities ranged from 0.63 in British Exmoor Horn to 0.77 in Albanian Ruda. South-eastern European and Middle-Eastern sheep breeds were significantly more variable than northwestern and western European breeds. An overall heterozygote deficiency (f) across all loci was observed (P < 0.001), while genetic differentiation (theta) was 5.7%. Principal component analysis and Bayesian model-based clustering indicate a south-east to north-west cline, but also revealed distinct groups of Middle-Eastern fat-tailed sheep, south-eastern European sheep and north-western/western European sheep. Within the last group, two less-distinct clusters comprised the Merino-type and Alpine breeds respectively. The incomplete demarcations of most clusters probably reflects cross-breeding and/or upgrading. 相似文献
47.
48.
Sonia Shah Marc?J. Bonder Riccardo?E. Marioni Zhihong Zhu Allan?F. McRae Alexandra Zhernakova Sarah?E. Harris Dave Liewald Anjali?K. Henders Michael?M. Mendelson Chunyu Liu Roby Joehanes Liming Liang BIOS Consortium Daniel Levy Nicholas G. Martin John M. Starr Cisca Wijmenga Naomi R. Wray Jian Yang Grant W. Montgomery Lude Franke Ian J. Deary Peter M. Visscher 《American journal of human genetics》2015,97(1):75-85
We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association studies on BMI (n ∼ 350,000) and height (n ∼ 250,000) to date. We derived methylation predictors by estimating probe-trait effects in discovery samples and tested them in external samples. Methylation profiles associated with BMI in older individuals from the Lothian Birth Cohorts (LBCs, n = 1,366) explained 4.9% of the variation in BMI in Dutch adults from the LifeLines DEEP study (n = 750) but did not account for any BMI variation in adolescents from the Brisbane Systems Genetic Study (BSGS, n = 403). Methylation profiles based on the Dutch sample explained 4.9% and 3.6% of the variation in BMI in the LBCs and BSGS, respectively. Methylation profiles predicted BMI independently of genetic profiles in an additive manner: 7%, 8%, and 14% of variance of BMI in the LBCs were explained by the methylation predictor, the genetic predictor, and a model containing both, respectively. The corresponding percentages for LifeLines DEEP were 5%, 9%, and 13%, respectively, suggesting that the methylation profiles represent environmental effects. The differential effects of the BMI methylation profiles by age support previous observations of age modulation of genetic contributions. In contrast, methylation profiles accounted for almost no variation in height, consistent with a mainly genetic contribution to inter-individual variation. The BMI results suggest that combining genetic and epigenetic information might have greater utility for complex-trait prediction. 相似文献
49.
Roberto Mendoza-Londono Somayyeh Fahiminiya Jacek Majewski CareRare Canada Consortium Martine Tétreault Javad Nadaf Peter Kannu Etienne Sochett Andrew Howard Jennifer Stimec Lucie Dupuis Paul Roschger Klaus Klaushofer Telma Palomo Jean Ouellet Hadil Al-Jallad John?S. Mort Pierre Moffatt Sergei Boudko Hans-Peter B?chinger Frank Rauch 《American journal of human genetics》2015,96(6):979-985
Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous variants in SPARC (GenBank: ; c.497G>A [p.Arg166His] in individual 1; c.787G>A [p.Glu263Lys] in individual 2). Published modeling and site-directed mutagenesis studies had previously shown that the residues substituted by these mutations form an intramolecular salt bridge in SPARC and are essential for the binding of SPARC to collagen type I. The amount of SPARC secreted by skin fibroblasts was reduced in individual 1 but appeared normal in individual 2. The migration of collagen type I alpha chains produced by these fibroblasts was mildly delayed on SDS-PAGE gel, suggesting some overmodification of collagen during triple helical formation. Pulse-chase experiments showed that collagen type I secretion was mildly delayed in skin fibroblasts from both individuals. Analysis of an iliac bone sample from individual 2 showed that trabecular bone was hypermineralized on the material level. In conclusion, these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans. NM_003118.3相似文献
50.
Hanan Shamseldin Anas?M. Alazami Melanie Manning Amal Hashem Oana Caluseiu Brahim Tabarki Edward Esplin Susan Schelley A.?Micheil Innes Jillian?S. Parboosingh Ryan Lamont CareRare Canada Consortium Jacek Majewski Francois?P. Bernier Fowzan?S. Alkuraya 《American journal of human genetics》2015,97(6):862-868
Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963∗] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration. 相似文献