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Exome sequencing, determining the DNA sequence of the protein-coding segments of all genes, is a useful test for identifying disease-causing genetic variations. Genome sequencing, determining the sequence of all of a person's DNA, can detect even more disease-causing genetic variations. But neither test can diagnose a genetic disease in a patient.
Diagnosis must be performed by a physician based on knowledge of an individual patient's medical history, family history, physical examination, imaging studies, and laboratory tests. Genotype-phenotype correlation is essential for diagnosing genetic disease in a patient known to carry a disease-associated genetic variant. For example, finding a R114W variant of the HNF4A gene on exome sequencing would confirm a diagnosis of MODY (maturity-onset diabetes of young people, an autosomal dominant condition)1 in a 25-year-old woman with type 2 diabetes and a strong family history of early-onset type 2 diabetes, but diabetes cannot be diagnosed in a different 25-year-old woman with normal glucose metabolism and no family history of diabetes who carries exactly the same genetic variant. The second woman’s risk of developing diabetes by age 40 years is estimated to be less than 10%.2
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Friedman JM, Jones KL, Carey JC. Exome Sequencing and Clinical Diagnosis. JAMA. Published online July 31, 2020. doi:10.1001/jama.2020.11126
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