ESPEYB16 14. Year in Science and Medicine 2019 (1) (18 abstracts)
14.13. Effect of genetic diagnosis on patients with previously undiagnosed disease
Splinter K , Adams DR , Bacino CA , Bellen HJ , Bernstein JA , Cheatle-Jarvela AM , Eng CM , Esteves C , Gahl WA , Hamid R , Jacob HJ , Kikani B , Koeller DM , Kohane IS , Lee BH , Loscalzo J , Luo X , McCray AT , Metz TO , Mulvihill JJ , Nelson SF , Palmer CGS , Phillips JA , 3rd , Pick L , Postlethwait JH , Reuter C , Shashi V , Sweetser DA , Tifft CJ , Walley NM , Wangler MF , Westerfield M , Wheeler MT , Wise AL , Worthey EA , Yamamoto S & Ashley EA
Undiagnosed Diseases Network, Harvard Medical School, Brigham and Women’s Hospital, and Massachusetts General Hospital, Boston, USA
To read the full abstract: N Engl J Med 2018;379:2131–2139.
The authors reviewed data on 1519 patients referred to the Undiagnosed Diseases Network (UDN), a US NIH funded network linking seven clinical sites. 53% of patients were female and their symptoms were neurologic (40%), musculoskeletal (10%), immunological (7%), gastrointestinal (7%), or rheumatological (6%). Of the 382 patients who had a complete evaluation, the UDN was able to establish the diagnosis in 132 (35%), many of which resulted in changes in management. 31 new syndromes were defined.
The cost of human whole-genome or whole-exome genome sequencing is falling drastically. Having been solely a research tool for some well-funded investigators, it now has a rapidly increasing place in clinical practice with tangible and even cost-effective benefits. In this study, changes in management occurred in 21% of those patients with a positive diagnosis, including use of medications, vitamin, coenzyme therapy and organ transplantation. Other types of benefit include genetic counselling, changes in prognosis and avoidance of other possibly extensive and invasive diagnostic testing. Furthermore, the benefits of genome sequencing will be cumulative – many patients with genome sequence results will initially have no diagnosis, but as patterns build across patients with similar phenotypes and gene mutations, new syndromes will be defined and new genes will be established as causes of existing disorders.
A particular strength of the network described here was the inclusion of a model organism screening facility, to test the functional relevance of new human mutations. For example, a novel mutation in NR5A1 (steroidogenic factor-1) was shown to alter gene function when experimentally introduced into drosophila, and hence confirmed as a novel cause of 46,XX DSD in the proband and additional patients.
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ESPE Yearbook of Paediatric Endocrinology
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