2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Diagnoses Made Following Non-Diagnostic NGS testing: One UDN Clinical Site's Experience

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This study focused on the experiences of the Duke/Columbia clinical site of the Undiagnosed Diseases Network (UDN) in diagnosing patients who had undergone non-diagnostic exome sequencing (ES). They reviewed a cohort of resolved cases that entered the UDN with non-diagnostic ES between July 2015 and November 2022. A total of 57 cases were included, with 46 having undergone clinical exome sequencing and 11 research exomes. The study aimed to describe the modalities that achieved diagnosis, the types of diagnoses/variants identified, and the reasons why these diagnoses had not been reported previously.<br /><br />The study presented a case example to illustrate the value of UDN research analyses. In this case, a patient with macrocephaly, hypotonia, developmental delay, and involuntary movements resembling Parkinsonism had previously undergone non-diagnostic clinical trio ES and UDN clinical trio genome sequencing. However, research analysis at the Duke UDN clinical site on the prior sequencing data identified compound heterozygous variants in the WARS2 gene as the diagnostic findings. This research analysis prioritized these variants based on segregation testing and follow-up functional work. The variants had not been prioritized in the initial clinical sequencing due to the allele frequency of the maternal allele and the lack of a phenotypic overlap between the patient and the published phenotype.<br /><br />The Duke UDN clinical site had a higher diagnosis rate for patients with prior non-diagnostic ES compared to previous reports. This was attributed to the personalized modalities used by the site for resolution, instead of reflexively moving on to genome sequencing. Re-analysis of the prior ES data using a phenotypic agnostic, bioinformatics-driven pipeline resulted in one-third of the diagnoses in these ES-negative cases. Additionally, research analysis of the genome sequencing data led to additional diagnoses in novel genes. Overall, the Duke UDN clinical site activities accounted for 68% of all diagnoses.<br /><br />The study highlighted the importance of investigating and interrogating existing ES data to conserve resources, particularly in the context of high medical costs and insurance reimbursements. The authors suggested that further investigation in this area is warranted.

Asset Subtitle

Presenting Author - Rebecca C. Spillmann, MS, CGC; Co-Author - Kelly Schoch, MS, CGC; Co-Author - Queenie Khoon Ghee Tan, MD, PhD; Co-Author - Vandana Shashi, MD;

Meta Tag

Exome sequencing

Genetic Testing

Genome sequencing

Identification of Disease Genes

NextGen Sequencing

Sequencing

Co-Author Kelly Schoch, MS, CGC

Co-Author Queenie Khoon Ghee Tan, MD, PhD

Co-Author Vandana Shashi, MD

Presenting Author Rebecca C. Spillmann, MS, CGC

Keywords

Undiagnosed Diseases Network

non-diagnostic exome sequencing

clinical exome sequencing

research exomes

diagnosis

variants

UDN research analyses

WARS2 gene

diagnosis rate

genome sequencing