New Perspectives for the Elucidation of Genetic Disorders
2007; Elsevier BV; Volume: 81; Issue: 2 Linguagem: Inglês
10.1086/520679
ISSN1537-6605
Autores Tópico(s)Genomic variations and chromosomal abnormalities
ResumoFor almost 15 years, genome research has focused on the search for major risk factors in common diseases, with disappointing results. Only recently, whole-genome association studies have begun to deliver because of the introduction of high-density single-nucleotide–polymorphism arrays and massive enlargement of cohort sizes, but most of the risk factors detected account for only a small proportion of the total genetic risk, and their diagnostic value is negligible. There is reason to believe that the complexity of many "multifactorial" disorders is primarily due to genetic heterogeneity, with defects of different genes causing the same disease. Moreover, de novo copy-number variation has been identified as a major cause of mental retardation and other complex disorders, suggesting that new mutations are an important, previously overlooked factor in the etiology of complex diseases. These observations support the notion that research into the previously neglected monogenic disorders should become a priority of genome research. Because of the introduction of novel high-throughput, low-cost sequencing methods, sequencing and genotyping will soon converge, with far-reaching implications for the elucidation of genetic disease and health care. For almost 15 years, genome research has focused on the search for major risk factors in common diseases, with disappointing results. Only recently, whole-genome association studies have begun to deliver because of the introduction of high-density single-nucleotide–polymorphism arrays and massive enlargement of cohort sizes, but most of the risk factors detected account for only a small proportion of the total genetic risk, and their diagnostic value is negligible. There is reason to believe that the complexity of many "multifactorial" disorders is primarily due to genetic heterogeneity, with defects of different genes causing the same disease. Moreover, de novo copy-number variation has been identified as a major cause of mental retardation and other complex disorders, suggesting that new mutations are an important, previously overlooked factor in the etiology of complex diseases. These observations support the notion that research into the previously neglected monogenic disorders should become a priority of genome research. Because of the introduction of novel high-throughput, low-cost sequencing methods, sequencing and genotyping will soon converge, with far-reaching implications for the elucidation of genetic disease and health care. Until the early '90s, the project to sequence the human genome was driven by the expectation that it would pave the way for the elucidation of all known Mendelian disorders (e.g., see the work of Guyer and Collins1Guyer MS Collins FS The Human Genome Project and the future of medicine.Am J Dis Child. 1993; 147: 1145-1152PubMed Google Scholar and references therein). Later, expectations were raised further by optimistic statements of leading genome researchers about the impact of this research for common disorders like coronary heart disease, stroke, dementia, psychiatric disorders, asthma, and cancer. For the pharmaceutical industry and for politicians alike, these prospects were extremely attractive. This was the reason why the search for genetic causes of complex diseases has received highest priority worldwide. On the basis of the assumption that most frequent disorders are multifactorial—that is, due to an interplay of genetic and nongenetic factors—and that hereditary risk factors for common diseases are evolutionarily old,2Ghosh S Collins FS The geneticist's approach to complex disease.Annu Rev Med. 1996; 47: 333-353Crossref PubMed Scopus (55) Google Scholar, 3Risch N Merikangas K The future of genetic studies of complex human diseases.Science. 1996; 273: 1516-1517Crossref PubMed Scopus (4160) Google Scholar, 4Cardon LR Bell JI Association study designs for complex diseases.Nat Rev Genet. 2001; 2: 91-99Crossref PubMed Scopus (1139) Google Scholar, 5Terwilliger JD Weiss KM Linkage disequilibrium mapping of complex disease: fantasy or reality?.Curr Opin Biotechnol. 1998; 9: 578-594Crossref PubMed Scopus (281) Google Scholar industry and government agencies have spent billions of dollars to search for associated DNA variants in the human genome that are more common in patients with specific complex disorders than in healthy individuals. However, genomewide association studies have often yielded contradictory results, which was generally ascribed to insufficient cohort sizes and marker densities,6Ioannidis JP Trikalinos TA Ntzani EE Contopoulos-Ioannidis DG Genetic associations in large versus small studies: an empirical assessment.Lancet. 2003; 361: 567-571Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar, 7Lohmueller KE Pearce CL Pike M Lander ES Hirschhorn JN Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.Nat Genet. 2003; 33: 177-182Crossref PubMed Scopus (1583) Google Scholar, 8Gibbs RA Deeper into the genome.Nature. 2005; 437: 1233-1234Crossref PubMed Scopus (26) Google Scholar, 9Jorgenson E Witte JS A gene-centric approach to genome-wide association studies.Nat Rev Genet. 2006; 7: 885-891Crossref PubMed Scopus (78) Google Scholar and, apart from a few notable exceptions (e.g., the work of Klein et al.10Klein RJ Zeiss C Chew EY Tsai J-Y Sackler RS Haynes C Henning AK SanGiovanni JP Mane SM Mayne ST et al.Complement factor H polymorphism in age-related macular degeneration.Science. 2005; 308: 385-389Crossref PubMed Scopus (3306) Google Scholar), major risk factors for complex disorders have remained elusive. Recent studies have shown that even mildly deleterious, evolutionarily old mutations are unlikely to have survived as common polymorphisms in the human population.11Kryukov GV Pennacchio LA Sunyaev SR Most rare missense alleles are deleterious in humans: implications for complex disease and association studies.Am J Hum Genet. 2007; 80: 727-739Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar Thus, most of the genetic risk for common disease must be conferred by low-frequency alleles, as suggested elsewhere12Pritchard JK Are rare variants responsible for susceptibility to complex diseases?.Am J Hum Genet. 2001; 69: 124-137Abstract Full Text Full Text PDF PubMed Scopus (879) Google Scholar, 13Pritchard JK Cox NJ The allelic architecture of human disease genes: common disease—common variant…or not?.Hum Mol Genet. 2002; 11: 2417-2423Crossref PubMed Scopus (526) Google Scholar and empirically confirmed—for example, for high-density lipoprotein levels in plasma.14Cohen JC Kiss RS Pertsemlidis A Marcel YL McPherson R Hobbs HH Multiple rare alleles contribute to low plasma levels of HDL cholesterol.Science. 2004; 305: 869-872Crossref PubMed Scopus (874) Google Scholar Identification of rare risk alleles, either directly or through association, requires a dense network of polymorphic markers. Closely linked genetic markers are often transmitted as evolutionarily conserved haplotype blocks.15Gabriel SB Schaffner SF Nguyen H Moore JM Roy J Blumenstiel B Higgins J DeFelice M Lochner A Faggart M et al.The structure of haplotype blocks in the human genome.Science. 2002; 296: 2225-2229Crossref PubMed Scopus (4532) Google Scholar To maximize the resolution of whole-genome association studies and to limit the number of markers that have to be typed, the International HapMap Project generated dense genomewide maps of SNPs and has characterized the linkage disequilibrium among them. According to recent estimates, however, comprehensive haplotype-based genomewide association studies still require typing of several hundred thousand of the ∼6 million validated SNPs that are currently known (see National Center for Biotechnology Information dbSNP, build 127, March 2007). This number is much larger than originally expected but still manageable because of the availability of DNA arrays that allow typing of >500,000 SNPs in a single experiment.16Zaitlen N Kang HM Eskin E Halperin E Leveraging the HapMap correlation structure in association studies.Am J Hum Genet. 2007; 80: 683-691Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Array-based SNP typing and analysis of large cohorts of patients and controls have significantly enhanced the power of association studies; very recently, this has led to the identification of genetic risk factors for various complex disorders, including type 2 diabetes, myocardial infarction, prostate cancer, Crohn disease, and obesity.17McPherson R Pertsemlidis A Kavaslar N Stewart A Roberts R Cox DR Hinds DA Pennacchio LA Tybjaerg-Hansen A Folsom AR et al.A common allele on chromosome 9 associated with coronary heart disease.Science. 2007; 316: 1488-1491Crossref PubMed Scopus (1367) Google Scholar, 18Helgadottir A Thorleifsson G Manolescu A Gretarsdottir S Blondal T Jonasdottir A Jonasdottir A Sigurdsson A Baker A Palsson A et al.A common variant on chromosome 9p21 affects the risk of myocardial infarction.Science. 2007; 316: 1491-1493Crossref PubMed Scopus (1230) Google Scholar, 19Rioux JD Xavier RJ Taylor KD Silverberg MS Goyette P Huett A Green T Kuballa P Barmada MM Datta LW et al.Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.Nat Genet. 2007; 39: 596-604Crossref PubMed Scopus (1395) Google Scholar, 20Haiman CA Patterson N Freedman ML Myers SR Pike MC Waliszewska A Neubauer J Tandon A Schirmer C McDonald GJ et al.Multiple regions within 8q24 independently affect risk for prostate cancer.Nat Genet. 2007; 39: 638-644Crossref PubMed Scopus (534) Google Scholar, 21Gudmundsson J Sulem P Manolescu A Amundadottir LT Gudbjartsson D Helgason A Rafnar T Bergthorsson JT Agnarsson BA Baker A et al.Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24.Nat Genet. 2007; 39: 631-637Crossref PubMed Scopus (688) Google Scholar, 22Yeager M Orr N Hayes RB Jacobs KB Kraft P Wacholder S Minichiello MJ Fearnhead P Yu K Chatterjee N et al.Genome-wide association study of prostate cancer identifies a second risk locus at 8q24.Nat Genet. 2007; 39: 645-649Crossref PubMed Scopus (908) Google Scholar, 23Frayling TM Timpson NJ Weedon MN Zeggini E Freathy RM Lindgren CM Perry JRB Elliott KS Lango H Rayner NW et al.A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.Science. 2007; 316: 889-894Crossref PubMed Scopus (3042) Google Scholar, 24Dina C Meyre D Gallina S Durand E Körner A Jacobson P Carlsson LMS Kiess W Vatin V Lecoeur C et al.Variation in FTO contributes to childhood obesity and severe adult obesity.Nat Genet. 2007; 39: 724-726Crossref PubMed Scopus (1141) Google Scholar Moreover, pooling strategies have been developed that drastically reduce the costs of such investigations.25Pearson JV Huentelman MJ Halperin RF Tembe WD Melquist S Homer N Brun M Szelinger S Coon KD Zismann VL et al.Identification of the genetic basis for complex disorders by use of pooling-based genomewide single-nucleotide-polymorphism association studies.Am J Hum Genet. 2007; 80: 126-139Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar After the long, futile search for such risk factors, these developments have been greeted with elation and relief, but, in view of the growing euphoria, it may be necessary to put these results into perspective. So far, the identification of these novel risk factors has not shed much light on the pathogenesis of the relevant complex diseases. Many of the associated markers were found in noncoding regions17McPherson R Pertsemlidis A Kavaslar N Stewart A Roberts R Cox DR Hinds DA Pennacchio LA Tybjaerg-Hansen A Folsom AR et al.A common allele on chromosome 9 associated with coronary heart disease.Science. 2007; 316: 1488-1491Crossref PubMed Scopus (1367) Google Scholar, 18Helgadottir A Thorleifsson G Manolescu A Gretarsdottir S Blondal T Jonasdottir A Jonasdottir A Sigurdsson A Baker A Palsson A et al.A common variant on chromosome 9p21 affects the risk of myocardial infarction.Science. 2007; 316: 1491-1493Crossref PubMed Scopus (1230) Google Scholar, 19Rioux JD Xavier RJ Taylor KD Silverberg MS Goyette P Huett A Green T Kuballa P Barmada MM Datta LW et al.Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.Nat Genet. 2007; 39: 596-604Crossref PubMed Scopus (1395) Google Scholar, 20Haiman CA Patterson N Freedman ML Myers SR Pike MC Waliszewska A Neubauer J Tandon A Schirmer C McDonald GJ et al.Multiple regions within 8q24 independently affect risk for prostate cancer.Nat Genet. 2007; 39: 638-644Crossref PubMed Scopus (534) Google Scholar, 21Gudmundsson J Sulem P Manolescu A Amundadottir LT Gudbjartsson D Helgason A Rafnar T Bergthorsson JT Agnarsson BA Baker A et al.Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24.Nat Genet. 2007; 39: 631-637Crossref PubMed Scopus (688) Google Scholar, 22Yeager M Orr N Hayes RB Jacobs KB Kraft P Wacholder S Minichiello MJ Fearnhead P Yu K Chatterjee N et al.Genome-wide association study of prostate cancer identifies a second risk locus at 8q24.Nat Genet. 2007; 39: 645-649Crossref PubMed Scopus (908) Google Scholar or in genes with unknown function,23Frayling TM Timpson NJ Weedon MN Zeggini E Freathy RM Lindgren CM Perry JRB Elliott KS Lango H Rayner NW et al.A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.Science. 2007; 316: 889-894Crossref PubMed Scopus (3042) Google Scholar, 24Dina C Meyre D Gallina S Durand E Körner A Jacobson P Carlsson LMS Kiess W Vatin V Lecoeur C et al.Variation in FTO contributes to childhood obesity and severe adult obesity.Nat Genet. 2007; 39: 724-726Crossref PubMed Scopus (1141) Google Scholar and, in other studies, the responsible sequence variants could not be precisely mapped because of limited resolution of association and linkage analysis. Moreover, most of these factors account for only a small proportion of the total genetic risk, and their presence or absence will rarely increase or reduce the recurrence risk for the relevant disorder more than twofold. In contrast, being the sibling of a patient with a complex disorder such as schizophrenia, type 1 diabetes, or cleft lip and palate will raise the recurrence risk 10- to 40-fold above the population risk. These recently identified genetic risk factors are thus of no diagnostic and little prognostic value. This will change only if most other genetic risk factors are determined—and, even then, only if and when typing of all these factors becomes part of the diagnostic routine, which is not likely to happen in the near future.26Cox DR (2007) Association of human DNA variation with complex traits. Plenary abstract 12 presented at the Human Genome Meeting, Montreal, May 24Google Scholar Insufficient sample sizes and marker densities are not the only problems complicating the search for genetic factors that are associated with complex disorders. In fact, there are more fundamental reasons why this strategy can meet with only limited success. One of these is genetic heterogeneity, which accounts for the complexity of many "multifactorial" disorders.27Passarge E Wither polygenic inheritance: mapping Hirschsprung disease.Nat Genet. 1993; 4: 325-326Crossref PubMed Scopus (23) Google Scholar The most extreme example of this is mental retardation (MR), the complex disorder with the highest socioeconomic costs in developed societies.28Roeleveld N Zielhuis GA Gabreels F The prevalence of mental retardation: a critical review of recent literature.Dev Med Child Neurol. 1997; 39: 125-132Crossref PubMed Scopus (329) Google Scholar, 29Ropers HH Hamel BC X-linked mental retardation.Nat Rev Genet. 2005; 6: 46-57Crossref PubMed Scopus (355) Google Scholar, 30Ropers HH X-linked mental retardation: many genes for a complex disorder.Curr Opin Genet Dev. 2006; 16: 260-269Crossref PubMed Scopus (128) Google Scholar Almost 300 different gene defects are known to give rise to MR,31Inlow JK Restifo LL Molecular and comparative genetics of mental retardation.Genetics. 2004; 166: 835-881Crossref PubMed Scopus (212) Google Scholar but their total number may run into the thousands, and most of them are still unknown (reviewed elsewhere,30Ropers HH X-linked mental retardation: many genes for a complex disorder.Curr Opin Genet Dev. 2006; 16: 260-269Crossref PubMed Scopus (128) Google Scholar and see the "Large-Scale Mutation Screening in MR and Other Diseases" section). Different single-gene defects have also been identified in a wide variety of other complex disorders, such as Alzheimer and Parkinson disease, breast and colon cancer, coronary heart disease, hypertension (reviewed by Peltonen et al.32Peltonen L Perola M Naukkarinen J Palotie A Lessons from studying monogenic disease for common disease.Hum Mol Genet. 2006; 15: R67-R74Crossref PubMed Scopus (64) Google Scholar and Campion33Campion D Dissection génétique des maladies à hérédité complexe.Médecine/Sciences. 2001; 17: 1139-1148Crossref Scopus (6) Google Scholar), and atopic dermatitis,34Sandilands A Terron-Kwiatkowski A Hull PR O'Regan GM Clayton TH Watson RM Carrick T Evans AT Liao H Zhao Y et al.Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.Nat Genet. 2007; 39: 650-654Crossref PubMed Scopus (474) Google Scholar, 35Palmer CNA Irvine AD Terron-Kwiatkowski A Zhao Y Liao H Lee SP Goudie DR Sandilands A Campbell LE Smith FJD et al.Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.Nat Genet. 2006; 38: 441-446Crossref PubMed Scopus (2089) Google Scholar and much of our present knowledge about the pathogenesis of complex disorders has come from the study of monogenic forms. Moreover, novel disease-causing gene defects may be much more common in these conditions than previously thought, as judged from the high number of de novo copy-number variants (CNVs) recently detected in various complex disorders (see the "CNV and Disease" section), and most of these mutations may be too short lived to be detectable by association studies. Thus, systematic resequencing of genes that have been implicated in related Mendelian disorders is a promising strategy for the identification of risk factors for complex diseases (see the Nature Genetics editorial36Editorial Genomics of common diseases.Nat Genet. 2007; 39: 569Crossref Scopus (1) Google Scholar). However, monogenic disorders are also important in their own right. To date, only ∼2,000 of the estimated 25,000 protein-coding human genes—and almost none of the many genes that do not code for protein—have been implicated in disease, and causative mutations are known for only 3,345 mapped disorders.37McKusick VA Mendelian Inheritance in Man and its online version, OMIM.Am J Hum Genet. 2007; 80: 588-604Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar It is clear, however, that this is just the tip of the iceberg. Disorders listed in OMIM are enriched for diseases that run in families, because isolated cases are much less likely to be identified as being genetic, particularly if there is no specific, recognizable clinical phenotype. Severe autosomal disorders with early onset are mostly sporadic, because affected patients will seldom reproduce, and, in countries with small family sizes and low consanguinity rates, most patients with recessive disorders will be sporadic cases too. In the mouse, most loss-of-function mutations seem to result in phenotypic abnormalities; only 3%–4% of the knockout mutations listed on the Frontiers in Bioscience Database of Gene Knockouts were phenotypically normal (discussed by Brinkman et al.38Brinkman RR Dubé M-P Rouleau GA Orr AC Samuels ME Human monogenic disorders—a source of novel drug targets.Nat Rev Genet. 2006; 7: 249-260Crossref PubMed Scopus (70) Google Scholar), and learning or memory was affected in 75% of mice with mutations inactivating postsynaptic density proteins (S. Grant, Sanger-Wellcome Centre, personal communication; see also the work of Pocklington et al.39Pocklington AJ Cumiskey M Armstrong JD Grant SGN The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour.Mol Syst Biol. 2006; 2: 2006.0023Crossref PubMed Scopus (96) Google Scholar). Thus, it is likely that the vast majority of single-gene defects that give rise to disease have not been identified yet. Still, in contrast to the mouse and other model organisms in which the effects of single-gene mutations are being explored in a systematic manner (e.g., see the Knockout Mouse Project), the elucidation of monogenic disorders in man lags behind. This is particularly puzzling because, for many disorders, even the closely related mouse is not a good model, since orthologous gene defects in the two species often fail to yield comparable phenotypes. Moreover, numerous complex traits, notably cognitive defects, are extremely difficult to study in model organisms. Thus, there are compelling arguments for putting more effort into the elucidation of human monogenic disorders,38Brinkman RR Dubé M-P Rouleau GA Orr AC Samuels ME Human monogenic disorders—a source of novel drug targets.Nat Rev Genet. 2006; 7: 249-260Crossref PubMed Scopus (70) Google Scholar, 40Antonarakis SE Beckmann JS Mendelian disorders deserve more attention.Nat Rev Genet. 2006; 7: 277-282Crossref PubMed Scopus (150) Google Scholar, 41O'Connor TP Crystal RG Genetic medicines: treatment strategies for hereditary disorders.Nat Rev Genet. 2006; 7: 261-276Crossref PubMed Scopus (124) Google Scholar which has been greatly facilitated by the availability of the entire sequence of the human genome. At present, a variety of efficient strategies are available for the study of Mendelian disorders, as discussed below, and several of these are also suitable for large-scale, systematic studies of apparently complex diseases. Disease-associated balanced chromosome rearrangements (DBCRs) truncating or otherwise inactivating genes form a visible bridge between human phenotypes and genotypes. Therefore, systematic breakpoint mapping and cloning in patients with balanced chromosome rearrangements has been proposed as an efficient strategy for elucidating the molecular causes of hereditary disease.42Tommerup N Mendelian cytogenetics: chromosome rearrangements associated with Mendelian disorders.J Med Genet. 1993; 30: 713-727Crossref PubMed Scopus (78) Google Scholar, 43Wirth J Nothwang HG van der Maarel S Menzel C Borck G Lopez-Pajares I Brøndum-Nielsen K Tommerup N Bugge M Ropers HH et al.Systematic characterisation of disease associated balanced chromosome rearrangements by FISH: cytogenetically and genetically anchored YACs identify microdeletions and candidate regions for mental retardation genes.J Med Genet. 1999; 36: 271-278PubMed Google Scholar, 44Bugge M Bruun-Petersen G Brøndum-Nielsen K Friedrich U Hansen J Jensen G Jensen PKA Kristoffersson U Lundsteen C Niebuhr E et al.Disease associated balanced chromosome rearrangements: a resource for large scale genotype-phenotype delineation in man.J Med Genet. 2000; 37: 858-865Crossref PubMed Google Scholar De novo DBCRs can be identified by conventional karyotyping, and, with an incidence of 1 in 2,000, they are not rare.45Warburton D De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints.Am J Hum Genet. 1991; 49: 995-1013PubMed Google Scholar About 6% of these are associated with clinical abnormalities such as MR with or without multiple congenital abnormalities (MCA), which is seen in almost half of these cases. In general, breakage events that give rise to DBCRs are not mediated by nonallelic homologous recombination,46Erdogan F Chen W Kirchhoff M Kalscheuer VM Hultschig C Müller I Schulz R Menzel C Bryndorf T Ropers HH et al.Impact of low copy repeats on the generation of balanced and unbalanced chromosomal aberrations in mental retardation.Cytogenet Genome Res. 2006; 115: 247-253Crossref PubMed Scopus (60) Google Scholar and they seem to occur everywhere in the human genome. An advantage of this approach is that breakpoints can be precisely mapped, in contrast to wide mapping intervals, which are characteristic of association and linkage studies and which have hampered the identification of the relevant genes. The Mendelian Cytogenetic Network and its database MCNdb have been instrumental in the identification of numerous X-linked and autosomal candidate genes for MR and other disorders—for example, in the course of systematic studies conducted at the Max Planck Institute for Molecular Genetics (Berlin) and the Wilhelm Johannsen Centre for Functional Genome Research (Copenhagen). Recently, similar programs to characterize DBCRs in a systematic fashion have also been initiated elsewhere.47Williamson RE Darrow KN Michaud S Jacobs JS Jones MC Eberl DF Maas RL Liberman MC Morton CC Methylthioadenosine phosphorylase (MTAP) in hearing: gene disruption by chromosomal rearrangement in a hearing impaired individual and model organism analysis.Am J Med Genet A. 2007; 143: 1630-1639Crossref Scopus (10) Google Scholar, 48Lu W Quintero-Rivera F Fan Y Alkuraya FS Donovan DJ Xi Q Turbe-Doan A Li QG Campbell CG Shanske AL et al.NFIA haploinsufficiency is associated with a CNS malformation syndrome and urinary tract defects.PLoS Genet. 2007; 3: e80Crossref PubMed Scopus (74) Google Scholar, 49Alkuraya FS Saadi I Lund JJ Turbe-Doan A Morton CC Maas RL SUMO1 haploinsufficiency leads to cleft lip and palate.Science. 2006; 313: 1751Crossref PubMed Scopus (137) Google Scholar Screening for submicroscopic deletions and duplications, with use of array-based comparative genomic hybridization (array CGH) and related methods, is a novel, powerful strategy for the identification of disease genes.50Vissers LELM Veltman JA Geurts van Kessel A Brunner HG Identification of disease genes by whole genome CGH arrays.Hum Mol Genet. 2005; 14: R215-R223Crossref PubMed Scopus (125) Google Scholar Array CGH was instrumental in finding the causative defects underlying several known malformation syndromes, including CHARGE (coloboma, heart anomaly, choanal atresia, retardation, genital, and ear anomalies),51Vissers LE van Ravenswaaij CM Admiraal R Hurst JA de Vries BB Janssen IM van der Vliet WA Huys EH de Jong PJ Hamel BC et al.Mutations in a new member of the chromodomain gene family cause CHARGE syndrome.Nat Genet. 2004; 36: 955-957Crossref PubMed Scopus (869) Google Scholar Peters-Plus,52Lesnik Oberstein SAJ Kriek M White SJ Kalf ME Szuhai K den Dunnen JT Breuning MH Hennekam RCM Peters plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase.Am J Hum Genet. 2006; 79 (erratum 79:985): 562-566Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar Pitt-Hopkins,53Zweier C Peippo MM Hoyer J Sousa S Bottani A Clayton-Smith J Reardon W Saraiva J Cabral A Göhring I et al.Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).Am J Hum Genet. 2007; 80: 994-1001Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 54Amiel J Rio M de Pontual L Redon R Malan V Boddaert N Plouin P Carter NP Lyonnet S Munnich A et al.Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.Am J Hum Genet. 2007; 80: 988-993Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar and thrombocytopenia-absent radius syndrome.55Klopocki E Schulze H Strauß G Ott CE Hall J Trotier F Fleischhauer S Greenhalgh L Newbury-Ecob R Neumann LM et al.Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius (TAR) syndrome.Am J Hum Genet. 2007; 80: 232-240Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar Moreover, thanks to high-resolution array-CGH screening, the catalogue of known genomic disorders is rapidly expanding,56Sharp AJ Hansen S Selzer RR Cheng Z Regan R Hurst JA Stewart H Price SM Blair E Hennekam RC et al.Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome.Nat Genet. 2006; 38: 1038-1042Crossref PubMed Scopus (479) Google Scholar, 57Sharp AJ Locke DP McGrath SD Cheng Z Bailey JA Vallente RU Pertz LM Clark RA Schwartz S Segraves R et al.Segmental duplications and copy-number variation in the human genome.Am J Hum Genet. 2005; 77: 78-88Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar, 58Lupski JR Stankiewicz P Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes.PLoS Genet. 2005; 1: e49Crossref PubMed Scopus (416) Google Scholar and array CGH–based comparative analysis of overlapping chromosome rearrangements is beginning to shed light on the underlying major genes. De novo genomic imbalances have been detected in 7% of patients with nonsyndromic MR, with use of tiling path BAC arrays,59de Vries BB Pfundt R Leisink M Koolen DA Vissers LELM Janssen IM van Reijmersdal S Nillesen WM Huys EHLPG de Leeuw N et al.Diagnostic genome profiling in mental retardation.Am J Hum Genet. 2005; 77: 606-616Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar and, in 10 of 100 mentally retarded patients studied with (Affymetrix 100k) high-density SNP typing arrays.60Friedman JM Bar
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