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Rare-disease genetics in the era of next-generation sequencing: discovery to translation

Key Points

  • 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.

Abstract

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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Figure 1: Pace of discovery of novel rare-disease-causing genes using whole-exome sequencing.
Figure 2: Gene identification approaches for different categories of rare diseases.
Figure 3: Rate of approval of orphan drug products.

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Acknowledgements

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.

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Summary of Disease-Causing Genes Identified by Exome Sequencing from 2009 - 2012 (XLS 103 kb)

Glossary

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.

Sibpair

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.

Hemimegalencephaly

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.

Supraphysiological

At levels greater than those normally found in the body.

Infraphysiological

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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