PT  - JOURNAL ARTICLE
AU  - Thomas Cloney
AU  - Lyndon Gallacher
AU  - Lynn S Pais
AU  - Natalie B Tan
AU  - Alison Yeung
AU  - Zornitza Stark
AU  - Natasha J Brown
AU  - George McGillivray
AU  - Martin B Delatycki
AU  - Michelle G de Silva
AU  - Lilian Downie
AU  - Chloe A Stutterd
AU  - Justine Elliott
AU  - Alison G Compton
AU  - Alysia Lovgren
AU  - Ralph Oertel
AU  - David Francis
AU  - Katrina M Bell
AU  - Simon Sadedin
AU  - Sze Chern Lim
AU  - Guy Helman
AU  - Cas Simons
AU  - Daniel G Macarthur
AU  - David R Thorburn
AU  - Anne H O'Donnell-Luria
AU  - John Christodoulou
AU  - Susan M White
AU  - Tiong Yang Tan
TI  - Lessons learnt from multifaceted diagnostic approaches to the first 150 families in Victoria’s Undiagnosed Diseases Program
AID  - 10.1136/jmedgenet-2021-107902
DP  - 2022 Aug 01
TA  - Journal of Medical Genetics
PG  - 748--758
VI  - 59
IP  - 8
4099  - http://jmg.bmj.com/content/59/8/748.short
4100  - http://jmg.bmj.com/content/59/8/748.full
SO  - J Med Genet2022 Aug 01; 59
AB  - 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.Data are available upon reasonable request.