Shortcutting the diagnostic odyssey: the multidisciplinary Program for Undiagnosed Rare Diseases in adults (UD-PrOZA)

Abstract

Background In order to facilitate the diagnostic process for adult patients suffering from a rare disease, the Undiagnosed Disease Program (UD-PrOZA) was founded in 2015 at the Ghent University Hospital in Belgium. In this study we report the five-year results of our multidisciplinary approach in rare disease diagnostics. Methods Patients referred by a healthcare provider, in which an underlying rare disease is likely, qualify for a UD-PrOZA evaluation. UD-PrOZA uses a multidisciplinary clinical approach combined with state-of-the-art genomic technologies in close collaboration with research facilities to diagnose patients. Results Between 2015 and 2020, 692 patients (94% adults) were referred of which 329 (48%) were accepted for evaluation. In 18% (60 of 329) of the cases a definite diagnosis was made. 88% (53 of 60) of the established diagnoses had a genetic origin. 65% (39 of 60) of the genetic diagnoses were made through whole exome sequencing (WES). The mean time interval between symptom-onset and diagnosis was 19 years. Key observations included novel genotype–phenotype correlations, new variants in known disease genes and the identification of three new disease genes. In 13% (7 of 53), identifying the molecular cause was associated with therapeutic recommendations and in 88% (53 of 60), gene specific genetic counseling was made possible. Actionable secondary findings were reported in 7% (12 of 177) of the patients in which WES was performed. Conclusion UD-PrOZA offers an innovative interdisciplinary platform to diagnose rare diseases in adults with previously unexplained medical problems and to facilitate translational research.

Novel SYNGAP1 Variant in an Adult Individual Affected by Intellectual Disability and Epilepsy: A Cold Case Solved through Whole-Exome Sequencing

“…Therefore, many initiatives are being undertaken all over the world, with the aim of reaching a molecular diagnosis in individuals with NDD through WES analysis. However, these initiatives focus mainly on a pediatric cohort; consequently, data on the efficiency of WES analysis in adult individuals with unsolved disorders are lacking [Schuermans et al, 2022]. Although the onset of NDDs is during the early childhood, many affected individuals reach adulthood.…”

Ensuring timely genetic diagnosis in adults

“…Adults with undiagnosed genetic disorders wait an average of 19 years to receive an explanation for their symptoms and to receive targeted care. 1 Recently, this problem was highlighted in 3 CMAJ case reports of rare genetic diseases, namely acute intermittent porphyria, 2 hereditary angioedema 3 and familial Mediterranean fever. 4 These case reports highlight 5 key clinical situations that should trigger clinicians to start a genetic work-up.…”

“…[2][3][4] Suspicion of an underlying genetic diagnosis should be increased for adults with a history of seemingly unrelated diagnoses in multiple systems, particularly when the patient is in a different demographic than is typical for a particular condition or if they lack the expected risk factors. [1][2][3][4] In one of the related cases, the patient's previous incorrect diagnoses of appendicitis, pancreatitis and cholecystitis appeared to have been made in the absence of risk factors. 4 Atypical imaging or laboratory findings and lack of expected pathology further supported the possibility of a unifying genetic diagnosis.…”

Accélérer l’obtention d’un diagnostic génétique chez l’adulte

“…Les adultes atteints de troubles génétiques non diagnostiqués attendent en moyenne 19 ans avant de recevoir une explication à leurs symptômes et un traitement ciblé 1 . Récemment, 3 rapports de cas concernant des maladies génétiques rares publiés dans le JAMC ont illustré ce problème : porphyrie aiguë intermittente 2 , oedème de Quincke héréditaire 3 et fièvre méditerranéenne familiale 4 .…”

“…Il faut particulièrement soupçonner un diagnostic génétique sous-jacent chez l’adulte qui a des antécédents de diagnostics apparemment distincts affectant plusieurs systèmes et organes, et encore davantage quand la personne appartient à un groupe démographique chez lequel une maladie particulière est atypique ou en l’absence des facteurs de risque habituels 1 – 4 . Dans l’un des cas présentés, des diagnostics initiaux erronés d’appendicite, de pancréatite et de cholécystite auraient été posés alors qu’il n’y avait pas de facteurs de risque 4 .…”