Diagnostic delays in rare genetic disorders with neuropsychiatric manifestations: A systematic review

Abstract

A systematic review of case reports, case series, and case-control studies was conducted to quantify the diagnostic delay in 84 rare genetic diseases where neuropsychiatric symptoms may be primary or part of the early clinical presentation. Data abstracted from 1221 published articles encompassing 1838 individual cases revealed a mean diagnostic delay of 9.3 ± 8.7 years, with no significant improvement in time to diagnosis over the 65-year period from 1958 to 2023. Subanalysis of the most recent 10 years, 2014–2023, revealed no change in diagnostic delay, even when stratifying by genetic and other diagnostic tests. Neuropsychiatric symptoms were reported in 68 % of the included cases. Following a definitive diagnosis and optimized management of the underlying rare genetic disease, 66 % of individuals experienced an improvement in their neuropsychiatric symptoms. Despite increasing access to, and substantial advancement in, genetic and other testing, diagnostic delays remain lengthy for individuals affected by these rare genetic diseases. This often results in suboptimal management of the associated neuropsychiatric symptoms. Thus, earlier implementation of genetic testing and other diagnostic tools may reduce these delays, improving patient outcomes and alleviating the burden of diagnostic uncertainty.