Next-generation sequencing (NGS) and improved sequence analysis methods have markedly increased the rate of identification of genes that cause rare genetic diseases; as many as 3,500 genes might be discovered over the next decade and added to the 'atlas' of human rare diseases, vastly increasing our current state of knowledge.
The identification of these genes will make molecular diagnoses possible for patients with rare diseases and their families, allowing both invasive diagnostic investigations and ineffectual treatments to cease; this will also bring clearer prognoses, improved disease management, precise reproductive counselling and, for some, the prospect of effective therapies.
NGS-based rare-disease diagnosis will rapidly make the transition into clinical service, representing a valuable case study in the integration of this revolutionary technology for most other realms of medicine.
Efficient identification of the remaining rare-disease-causing genes will require an unprecedented level of cooperation and collaboration, as well as the infrastructure and informatic tools to share deep phenotypic data and genetic variation data on a large scale.
Molecular insight into the rapidly increasing number of rare diseases being discovered will bring both new therapeutic opportunities and challenges, the latter of which will require the rethinking of the funding and practice of rare-disease translational research. Creative drug discovery approaches configured to rely, as much as possible, on low-cost generalizable approaches will be needed.
Work over the past 25 years has resulted in the identification of genes responsible for ~50% of the estimated 7,000 rare monogenic diseases, and it is predicted that most of the remaining disease-causing genes will be identified by the year 2020, and probably sooner. This marked acceleration is the result of dramatic improvements in DNA-sequencing technologies and the associated analyses. We examine the rapid maturation of rare-disease genetic analysis and successful strategies for gene identification. We highlight the impact of discovering rare-disease-causing genes, from clinical diagnostics to insights gained into biological mechanisms and common diseases. Last, we explore the increasing therapeutic opportunities and challenges that the resulting expansion of the 'atlas' of human genetic pathology will bring.
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Carter, C. O. Monogenic disorders. J. Med. Genet. 14, 316–320 (1977).
Baird, P. A., Anderson, T. W., Newcombe, H. B. & Lowry, R. B. Genetic disorders in children and young adults: a population study. Am. J. Hum. Genet. 42, 677–693 (1988).
Yoon, P. W. et al. Contribution of birth defects and genetic diseases to pediatric hospitalizations. A population-based study. Arch. Pediatr. Adolesc. Med. 151, 1096–1103 (1997).
McCandless, S. E., Brunger, J. W. & Cassidy, S. B. The burden of genetic disease on inpatient care in a children's hospital. Am. J. Hum. Genet. 74, 121–127 (2004).
Dye, D. E. et al. The impact of single gene and chromosomal disorders on hospital admissions of children and adolescents: a population-based study. Public Health Genomics 14, 153–161 (2010).
McKusick, V. A. Mendelian Inheritance in Man and its online version, OMIM. Am. J. Hum. Genet. 80, 588–604 (2007).
Ayme, S., Urbero, B., Oziel, D., Lecouturier, E. & Biscarat, A. C. Information on rare diseases: the Orphanet project. Rev. Med. Interne 19, 376S–377S (in French) (1998).
Samuels, M. E. Saturation of the human phenome. Curr. Genom. 11, 482–499 (2010).
Cooper, D. N. et al. Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics. Hum. Mutat. 31, 631–655 (2010).
Bamshad, M. J. et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nature Rev. Genet. 12, 745–755 (2011).
Ng, S. B. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009). Using Freeman–Sheldon syndrome as a proof-of-concept, the authors demonstrate for the first time that WES of a small number of unrelated affected individuals can identify the disease-causing gene.
Ng, S. B. et al. Exome sequencing identifies the cause of a mendelian disorder. Nature Genet. 42, 30–35 (2010). The identification of DHODH as the causative gene for Miller syndrome is the first successful application of WES for the discovery of a gene causing a rare Mendelian disorder.
Hoischen, A. et al. De novo mutations of SETBP1 cause Schinzel–Giedion syndrome. Nature Genet. 42, 483–485 (2010). The first demonstration of WES as a means to identify de novo mutations in a rare clinical syndrome.
Sherry, S. T. et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 29, 308–311 (2001).
Abecasis, G. R. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
Altshuler, D. M. et al. Integrating common and rare genetic variation in diverse human populations. Nature 467, 52–58 (2010).
Cooper, G. M. & Shendure, J. Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data. Nature Rev. Genet. 12, 628–640 (2011).
Sunyaev, S. R. Inferring causality and functional significance of human coding DNA variants. Hum. Molec. Genet. 21, R10–R17 (2012).
Schuurs-Hoeijmakers, J. H. et al. Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia. Am. J. Hum. Genet. 91, 1073–1081 (2012).
Kalsoom, U. E. et al. Whole exome sequencing identified a novel zinc-finger gene ZNF141 associated with autosomal recessive postaxial polydactyly type A. J. Med. Genet. 50, 47–53 (2012).
Sankaran, V. G. et al. Exome sequencing identifies GATA1 mutations resulting in Diamond–Blackfan anemia. J. Clin. Invest. 122, 2439–2443 (2012).
Fiskerstrand, T. et al. Familial diarrhea syndrome caused by an activating GUCY2C mutation. N. Engl. J. Med. 366, 1586–1595 (2012).
Gibson, W. T. et al. Mutations in EZH2 cause Weaver syndrome. Am. J. Hum. Genet. 90, 110–118 (2011).
Hood, R. L. et al. Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating–Harbor syndrome. Am. J. Hum. Genet. 90, 308–313 (2012).
Lindhurst, M. J. et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 365, 611–619 (2011). The first application of WES to discover somatic de novo mutations as the cause of a genetic disorder.
Riviere, J. B. et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nature Genet. 44, 934–940 (2012).
Robinson, P. N. et al. The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease. Am. J. Hum. Genet. 83, 610–615 (2008).
Fernandez, B. A. et al. Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotype. BMC Med. Genet. 13, 111 (2012).
McMillan, H. J. et al. Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency. Orphanet J. Rare Dis. 7, 90 (2012).
Isidor, B. et al. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nature Genet. 43, 306–308 (2011).
Majewski, J. et al. Mutations in NOTCH2 in families with Hajdu–Cheney syndrome. Hum. Mutat. 32, 1114–1117 (2011).
Simpson, M. A. et al. Mutations in NOTCH2 cause Hajdu–Cheney syndrome, a disorder of severe and progressive bone loss. Nature Genet. 43, 303–305 (2011).
McDaniell, R. et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am. J. Hum. Genet. 79, 169–173 (2006).
Lee, J. H. et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nature Genet. 44, 941–945 (2012).
Tsurusaki, Y. et al. Mutations affecting components of the SWI/SNF complex cause Coffin–Siris syndrome. Nature Genet. 44, 376–378 (2012). Mutations in six of 15 genes encoding subunits of a single complex are found to be causal for Coffin–Siris syndrome.
Srour, M. et al. Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. Am. J. Hum. Genet. 90, 693–700 (2012).
Beaulieu, C. L. et al. A generalizable pre-clinical research approach for orphan disease therapy. Orphanet J. Rare Dis. 7, 39 (2012). A valuable review which discusses generalizable approaches to the therapeutic configuration for rare diseases.
Rilstone, J. J., Alkhater, R. A. & Minassian, B. A. Brain dopamine-serotonin vesicular transport disease and its treatment. N. Engl. J. Med. 368, 543–550 (2012). A novel disease-causing gene is identified for a rare neurological disease, and the new insight suggests a successful treatment.
Green, P. et al. Brown–Vialetto–Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54. Am. J. Hum. Genet. 86, 485–489 (2010).
Johnson, J. O., Gibbs, J. R., Van Maldergem, L., Houlden, H. & Singleton, A. B. Exome sequencing in Brown–Vialetto–van Laere syndrome. Am. J. Hum. Genet. 87, 567–569 (2010).
Johnson, J. O. et al. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain 135, 2875–2882 (2012).
Bosch, A. M. et al. The Brown–Vialetto–Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives. Orphanet J. Rare Dis. 7, 83 (2012).
Shimada, Y. et al. Proteasome inhibitors improve the function of mutant lysosomal α-glucosidase in fibroblasts from Pompe disease patient carrying c.546G>T mutation. Biochem. Biophys. Res. Commun. 415, 274–278 (2011). A therapeutic approach using protein stabilization; mutant α-glucosidase in patients with Pompe disease can be stabilized by treatment with a proteasome inhibitor.
Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development. Rare Diseases and Orphan Products: Accelerating Research and Development (ed. Field, M.J. & Boat, T.F.) (National Academies Press, 2010).
Ramsey, B. W. et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N. Engl. J. Med. 365, 1663–1672 (2011). The first effective therapy for a specific and comparatively rare subclass of cystic fibrosis.
Freimer, N. & Sabatti, C. The human phenome project. Nature Genet. 34, 15–21 (2003).
Oetting, W. S. et al. Getting ready for the Human Phenome Project: the 2012 forum of the Human Variome Project. Hum. Mutat. 34, 661–666 (2013).
Riggs, E. R. et al. Towards an evidence-based process for the clinical interpretation of copy number variation. Clin. Genet. 81, 403–412 (2012).
Maddatu, T. P., Grubb, S. C., Bult, C. J. & Bogue, M. A. Mouse Phenome Database (MPD). Nucleic Acids Res. 40, D887–894 (2012).
Cheng, K. C., Xin, X., Clark, D. P. & La Riviere, P. Whole-animal imaging, gene function, and the Zebrafish Phenome Project. Curr. Opin. Genet. Dev. 21, 620–629 (2011).
Mashimo, T., Voigt, B., Kuramoto, T. & Serikawa, T. Rat Phenome Project: the untapped potential of existing rat strains. J. Appl. Physiol. 98, 371–379 (2005).
Serikawa, T. et al. National BioResource Project-rat and related activities. Exp. Anim. 58, 333–341 (2009).
Hamosh, A. et al. PhenoDB: a new web-based tool for the collection, storage, and analysis of phenotypic features. Hum. Mutat. 34, 566–571 (2013).
Girdea, M. et al. PhenoTips: patient phenotyping software for clinical and research use. Hum. Mut. 34, 1057–1065 (2013).
Kingsmore, S. F. & Saunders, C. J. Deep sequencing of patient genomes for disease diagnosis: when will it become routine? Sci. Transl. Med. 3, 87ps23 (2011).
Katsanis, S. H. & Katsanis, N. Molecular genetic testing and the future of clinical genomics. Nature Rev. Genet. 14, 415–426 (2013).
Bell, C. J. et al. Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci. Transl. Med. 3, 65ra4 (2011).
Berg, J. S., Khoury, M. J. & Evans, J. P. Deploying whole genome sequencing in clinical practice and public health: meeting the challenge one bin at a time. Genet. Med. 13, 499–504 (2011).
Green, R. C. et al. Exploring concordance and discordance for return of incidental findings from clinical sequencing. Genet. Med. 14, 405–410 (2012). A valuable study providing recommendations about which specific conditions and types of genetic variants should be returned as incidental findings in clinical sequencing.
Bettens, K., Sleegers, K. & Van Broeckhoven, C. Genetic insights in Alzheimer's disease. Lancet Neurol. 12, 92–104 (2013).
Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499–503 (2012).
Leonard, H. & Wen, X. The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment. Retard. Dev. Disabil. Res. Rev. 8, 117–134 (2002).
Elsabbagh, M. et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 5, 160–179 (2012).
Veltman, J. A. & Brunner, H. G. De novo mutations in human genetic disease. Nature Rev. Genet. 13, 565–575 (2012).
Vissers, L. E. et al. A de novo paradigm for mental retardation. Nature Genet. 42, 1109–1112 (2010). The first study to identify de novo mutations as causative for intellectual disability using WES of unaffected parents–affected child trios.
de Ligt, J. et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012).
Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012).
Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).
O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012).
Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012).
Farooq, F., Balabanian, S., Liu, X., Holcik, M. & MacKenzie, A. p38 mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR. Hum. Mol. Genet. 18, 4035–4045 (2009).
Farooq, F. et al. Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway. J. Clin. Invest. 121, 3042–3050 (2011).
Akhurst, R. J. & Hata, A. Targeting the TGFβ signalling pathway in disease. Nature Rev. Drug Discov. 11, 790–811 (2012).
MacKenzie, A. & Boycott, K. MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367, 1364–1365 (2012).
Montiel-Equihua, C. A., Thrasher, A. J. & Gaspar, H. B. Gene therapy for severe combined immunodeficiency due to adenosine deaminase deficiency. Curr. Gene Ther. 12, 57–65 (2012).
Prasad, V. K. & Kurtzberg, J. Transplant outcomes in mucopolysaccharidoses. Semin. Hematol. 47, 59–69 (2009).
Nakamura, A. & Takeda, S. Exon-skipping therapy for Duchenne muscular dystrophy. Neuropathology 29, 494–501 (2009).
Axelrod, F. B. et al. Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia. Pediatr. Res. 70, 480–483 (2009).
Ohashi, T. Enzyme replacement therapy for lysosomal storage diseases. Pediatr. Endocrinol. Rev. 10, 26–34 (2012).
Malik, V. et al. Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy. Ann. Neurol. 67, 771–780 (2010).
de Lartigue, J. Tafamidis for transthyretin amyloidosis. Drugs Today (Barc.) 48, 331–337 (2012).
Wheeler, T. M. et al. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature 488, 111–115 (2012).
Mantha, N., Das, S. K. & Das, N. G. RNAi-based therapies for Huntington's disease: delivery challenges and opportunities. Ther. Deliv. 3, 1061–1076 (2012).
Wu, X. et al. MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1L613V mutation. J. Clin. Invest. 121, 1009–1025 (2011).
The authors thank the Finding of Rare Disease Genes (FORGE) Canada Consortium for providing the opportunity to explore the underpinnings of rare diseases with a spirit of national collaboration. They also thank J. Schwartzentruber, J. Majewski and C. Beaulieu for their insight and counsel into the best practices for the discovery of rare-disease-causing genes.
The authors declare no competing financial interests.
- Orphan drugs
Pharmaceutical agents developed for the treatment of a rare disease (often referred to as an orphan disease). The assignment of 'orphan' status is a matter of public policy and is possible in only some countries.
- Next-generation sequencing
(NGS). Highly parallel DNA-sequencing technologies that produce many hundreds of thousands or millions of short reads (25–500 bp) for a low cost and in a short time.
- Capture approaches
Technologies based on hybridization using RNA or DNA baits to target and enrich for a genomic region of interest for subsequent next-generation sequencing.
- Freeman–Sheldon syndrome
A rare genetic disease characterized by contractures of the hands and feet, oropharyngeal abnormalities and distinctive facial features, including a very small mouth, puckered lips and an H-shaped dimple on the chin.
- Miller syndrome
A rare genetic disease characterized by extensive facial and limb defects, including malar hypoplasia, down-slanting palpebral fissures, micrognathia, cleft lip and palate, cup-shaped ears, lower-lid ectropion, postaxial limb deficiencies and syndactyly.
- Schinzel–Giedion syndrome
A rare genetic disease characterized by severe mental retardation, distinctive facial features and multiple congenital malformations (including skeletal, genitourinary, renal and cardiac malformations).
- Isolated population
A group of individuals who are descended from a small number of settlers (founders) and remain genetically (reproductively) isolated.
- Compound heterozygous mutations
Two different mutations present in the same gene but arranged in trans, such that each copy of the gene in a diploid organism carries one of the mutations.
Two siblings with both parents in common.
- Postaxial polydactyly type A
A congenital anomaly characterized by fifth-digit duplications in hands and/or feet. In the type A disorder, the extra digit is well formed and articulates with the fifth or an extra metacarpal.
- Diamond–Blackfan anaemia
A rare genetic disease characterized by congenital erythroid aplasia and congenital anomalies, particularly of the upper limb and craniofacial regions.
- Gain-of-function effect
Pertaining to a mutation: the acquisition of a new and abnormal function by a gene product when the mutation is present in the heterozygous state.
- Weaver syndrome
A rare genetic disease characterized by pre- and postnatal overgrowth, accelerated osseous maturation, characteristic craniofacial appearance and developmental delay.
- Floating–Harbour syndrome
A rare genetic disease characterized by proportionate short stature, delayed bone age, delayed speech development and typical facial features.
- Mosaic mutations
Mutations that are present in only a proportion of cells in the body.
- Proteus syndrome
A rare genetic disease characterized by patchy or mosaic overgrowth and hyperplasia of various tissues and organs.
- Hajdu–Cheney syndrome
A rare skeletal disorder characterized by short stature, coarse and dysmorphic facial features, bowing of the long bones, vertebral anomalies, acroosteolysis and generalized osteoporosis.
- Alagille syndrome
A rare disease characterized by cholestasis (caused by bile duct paucity), congenital cardiac defects, posterior embryotoxon in the eye, typical facial features and butterfly vertebrae.
- Genetic heterogeneity
Pertaining to a phenotype: caused by the alteration of one of many different genes.
- Chromosomal microarray
An approach based on probe–target hybridization to detect amplifications or deletions of chromosomal regions in a patient's tissue.
- Post-zygotic mutations
Mutations that an organism acquires during its lifespan. Also known as somatic mutations.
- Megalencephaly–capillary malformation syndrome and megalencephaly–polymicrogyria–polydactyly–hydrocephalus syndromes
A class of rare genetic diseases characterized by congenital or early postnatal megalencephaly (large brain), prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies and connective tissue dysplasia.
A rare developmental malformation characterized by the enlargement of one-half of the brain. Also known as unilateral megalencephaly.
- Coffin–Siris syndrome
A rare genetic disease characterized by mental retardation, coarse facial features, hypertrichosis and hypoplastic or absent nails on the fifth fingers or toes.
- Joubert syndrome
A rare genetic disease characterized by hypotonia, developmental delay and hypoplasia of the cerebellar vermis with the characteristic neuroradiologic 'molar tooth sign'.
- Loss-of-function alleles
Alleles that partly or fully eliminate normal protein activity.
- Dominant negative
Pertaining to a mutation: having a negative impact on the biological function of the remaining wild-type gene product when the mutation is present in the heterozygous state.
At levels greater than those normally found in the body.
At levels below those normally found in the body.
- Pompe disease
A rare lysosomal storage disease characterized by cardiomyopathy and muscular weakness. Also known as glycogen storage disease type II.
- Deep phenotypic data
Data from the precise and comprehensive annotation of phenotypic abnormalities (clinical features) using a standard set of agreed descriptors (ontology).
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Boycott, K., Vanstone, M., Bulman, D. et al. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat Rev Genet 14, 681–691 (2013). https://doi.org/10.1038/nrg3555
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