Lessons learnt from multifaceted diagnostic approaches to the first 150 families in Victoria's Undiagnosed Diseases Program. Issue 8 (5th November 2021)

• Record Type: Journal Article
• Authors: Cloney, Thomas; Gallacher, Lyndon; Pais, Lynn S; Tan, Natalie B; Yeung, Alison; Stark, Zornitza; Brown, Natasha J; McGillivray, George; Delatycki, Martin B; de Silva, Michelle G; Downie, Lilian; Stutterd, Chloe A; Elliott, Justine; Compton, Alison G; Lovgren, Alysia; Oertel, Ralph; Francis, David; Bell, Katrina M; Sadedin, Simon; Lim, Sze Chern; Helman, Guy; Simons, Cas; Macarthur, Daniel G; Thorburn, David R; O'Donnell-Luria, Anne H; Christodoulou, John; White, Susan M; Tan, Tiong Yang
• Is Part Of: Journal of medical genetics. Volume 59:Issue 8(2022)
• Page Start: 748
• Page End: 758
• Publication Date: 2021-11-05
• Subjects: genomics -- genetics -- medical -- paediatrics -- genetic testing -- genetic techniques; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2021-107902
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Clinical exome sequencing typically achieves diagnostic yields of 30%–57.5% in individuals with monogenic rare diseases. Undiagnosed diseases programmes implement strategies to improve diagnostic outcomes for these individuals. Aim: We share the lessons learnt from the first 3 years of the Undiagnosed Diseases Program-Victoria, an Australian programme embedded within a clinical genetics service in the state of Victoria with a focus on paediatric rare diseases. Methods: We enrolled families who remained without a diagnosis after clinical genomic (panel, exome or genome) sequencing between 2016 and 2018. We used family-based exome sequencing (family ES), family-based genome sequencing (family GS), RNA sequencing (RNA-seq) and high-resolution chromosomal microarray (CMA) with research-based analysis. Results: In 150 families, we achieved a diagnosis or strong candidate in 64 (42.7%) (37 in known genes with a consistent phenotype, 3 in known genes with a novel phenotype and 24 in novel disease genes). Fifty-four diagnoses or strong candidates were made by family ES, six by family GS with RNA-seq, two by high-resolution CMA and two by data reanalysis. Conclusion: We share our lessons learnt from the programme. Flexible implementation of multiple strategies allowed for scalability and response to the availability of new technologies. Broad implementation of family ES with research-based analysis showed promising yields post a negative clinical singleton ES. RNA-seq offered multiple benefits in family ES-negative populations. International data sharing strategies were critical in facilitating collaborations to establish novel disease–gene associations. Finally, the integrated approach of a multiskilled, multidisciplinary team was fundamental to having diverse perspectives and strategic decision-making.