Oct 4, 2013

Clinical whole-exome sequencing for the diagnosis of mendelian disorders

The New England Journal of Medicine
Yaping YangChristine M Eng


Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders. We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic phenotypes. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had autosomal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant...Continue Reading

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  • Citations605


Mentioned in this Paper

Genetic Disorders Screening
Genetic Screening Method
Genetic Conditions, Dominant
Thyroid Hormone Plasma Membrane Transport Defect
Conditions, Recessive Genetic
Parkinsonian Disorders
Parkinson Disease 1, Autosomal Dominant (Disorder)
Autosomal Dominant Inheritance

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