Saturation of the Human Phenome

Samuels, Mark E.

doi:10.2174/138920210793175886

Cited by 27 publications

(13 citation statements)

References 237 publications

(151 reference statements)

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“…1 To date, about 7000 different rare diseases are known and a substantially higher number of undefined phenotypes is presumed. 2 Essentially, 80% of rare diseases are of monogenic origin, and constitute a lifelong risk and a significant burden for the health systems. 3 Despite high standards in genetic clinics, half of the patients who receive conventional clinical evaluation and targeted genetic testing remain without specific diagnosis even after extensive workup.…”

Section: Introductionmentioning

confidence: 99%

Clinical exome sequencing: results from 2819 samples reflecting 1000 families

et al. 2016

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We report our results of 1000 diagnostic WES cases based on 2819 sequenced samples from 54 countries with a wide phenotypic spectrum. Clinical information given by the requesting physicians was translated to HPO terms. WES processes were performed according to standardized settings. We identified the underlying pathogenic or likely pathogenic variants in 307 families (30.7%). In further 253 families (25.3%) a variant of unknown significance, possibly explaining the clinical symptoms of the index patient was identified. WES enabled timely diagnosing of genetic diseases, validation of causality of specific genetic disorders of PTPN23, KCTD3, SCN3A, PPOX, FRMPD4, and SCN1B, and setting dual diagnoses by detecting two causative variants in distinct genes in the same patient. We observed a better diagnostic yield in consanguineous families, in severe and in syndromic phenotypes. Our results suggest that WES has a better yield in patients that present with several symptoms, rather than an isolated abnormality. We also validate the clinical benefit of WES as an effective diagnostic tool, particularly in nonspecific or heterogeneous phenotypes. We recommend WES as a first-line diagnostic in all cases without a clear differential diagnosis, to facilitate personal medical care.

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Section: Introductionmentioning

confidence: 99%

Clinical exome sequencing: results from 2819 samples reflecting 1000 families

et al. 2016

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“…Most rare diseases are genetic in origin; the precise number is unknown, but best estimates suggest that there are at least 7,000, and possibly many more, rare genetic diseases. 2,3 An early and accurate genetic diagnosis is critical to the optimal care for a child with a rare genetic disease and their family. However, diagnosis of a rare genetic disease can be a challenge and is clearly contingent upon understanding the molecular etiology of the disease.…”

Section: Introductionmentioning

confidence: 99%

FORGE Canada Consortium: Outcomes of a 2-Year National Rare-Disease Gene-Discovery Project

Beaulieu

Majewski

Schwartzentruber

et al. 2014

The American Journal of Human Genetics

235

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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.

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“…In aggregate, they present great healthcare challenges, contributing significantly to morbidity, mortality, and cost of care. Although the genes responsible for approximately 4000 distinct monogenic human diseases are known (Online Mendelian Inheritance in Man), recent estimates suggest that over 9000 single-gene phenotypes will ultimately be recognized and molecularly defined (Samuels 2010). Diseasecausing genes that had eluded discovery because of their rarity, clinical heterogeneity, and the paucity of families with multiple individuals affected by a specific disease, are being increasingly identified by NGS approaches (Figure 1).…”

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confidence: 99%