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The well-documented article by Uflacker et al1 shows the 2 sides of genetic progress with presymptomatic diagnosis2 foretelling tragic prion disease3,4 and preimplantation genetic diagnosis (PGD)5,6 allowing selection of unaffected offspring. This 2-edged sword also cuts across modern genetic testing, in which the benefits of comprehensive screening by microarray analysis7 and rapid NextGen sequencing8 are tempered by high costs, unequal access, and the uncertain consequences of nucleotide change. One major challenge is to distinguish disease-causing (pathogenic) mutations from benign variations (polymorphisms), an issue not faced by the patient of Uflacker et al,1 since her prion protein PRNP F198S amino acid substitution (phenylalanine to serine at position 198) had been observed in other patients with spongiform encephalopathy (SE).3,4 Applicable to their report1 is the even greater challenge for gene test interpretation posed by multifactorial determination (interaction of multiple genes plus environment to cause disease), the usual mechanism for common diseases like epilepsy9 but also operative when identical single-gene mutations cause variable outcomes within and among families.
Wilson GN. Presymptomatic and Preimplantation Genetic DiagnosisNeurology, NextGenetics, and the Next Generation. JAMA Neurol. 2014;71(4):403-404. doi:10.1001/jamaneurol.2013.5834