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Genome Sequencing (GS) as a First Test in a Genetics Clinic for Adults.

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical-Adult
  • Secondary Categories:
    • Clinical-Adult & Pediatric
Introduction
The American College of Medical Genetics and Genomics (ACMG) recommends genome sequencing (GS) testing as an effective strategy in comparison with single or multi-gene testing in patients with 1) a strong family history of a likely genetic disorder or otherwise unspecified phenotype, 2) known but heterogeneous disorder, or 3) in affected patients with previously non-conclusive genetic results (1). Genome sequencing (GS) is becoming the preferred method for molecular genetic diagnosis of rare and unknown diseases, capturing most genomic variation and eliminating the need for sequential genetic testing especially in patients with unknown etiology disorders (2).

Case Presentation
We launched a new general genetics clinic for adults at Providence Hospital in the Los Angeles metropolitan area in January 2023. In this clinic, patients with personal or family history of cancer or abnormal cancer genetic test were excluded. Indications for clinical evaluation included unknown etiology disorders, medical odyssey, complex or multiple common problems or disorders, heart failure, cardiomyopathy, lipid disorders, complex vascular abnormalities, aneurysms, arrhythmias, sudden cardiac death, connective tissue disorders, neurogenetic conditions, dementia, ataxia, epilepsy, undiagnosed pediatriconset disorders in adults, developmental delay with or without morphological features, Autism-spectrum disorders, cognitive disorders, unknown etiology proteinuria or renal failure, hearing loss, vision loss, amyloidosis, and other.



We evaluated 929 adult patients from January 2023 to October 2024. From total patients, 635 were new (68.35%), mostly females 671 (72.23%), with an average age of 52.5 years (17-88). 145 encounters were virtual (15.61%). After pretest genetic counseling and full consent, we ordered 533 genetic tests (57.37%) including mainly multigene panels and 71 GS (13.33%). Five GS tests are pending but generally the results were available in 4 weeks after the visit. Female patients were keener to ask for a GS (48/71 or 67.6%) with an average age of 47.42 years (18-81).



 

Diagnostic Workup
Results:

• Pathogenic variants: 22 in 66 resulted GS to date or 33.33%. One was a rare structural genome variant.

• Variants of uncertain significance (VUS): 19 in 66 or 28.78%. Three were converted to likely-pathogenic after clinical reevaluation.

• Negative: 25 in 66 or 37.89%

In addition, we identified 41 healthy carriers of autosomal recessive disease and 10 APOE positive cases. We identified pharmacogenetic results (class IA) in 99 % of cases.

Treatment and Management
All patients with a positive GS result had appropriate genetic counseling, offered management recommendations, and referred to their primary care providers, specialists, and multidisciplinary clinics for further care.

Outcome and Follow-Up
Our patients were appreciative of the clinical service and overall experience including those with a VUS or negative results. About 27% of patients with inconclusive results were interested in annual GS reanalysis or in case of a future personal or family history change.

Discussion
We have evaluated 71 patients with GS as a first test in this clinic. We have performed about 670 GS in children and adults from 2018 to 2023 in two previous institutions. In our brief experience, adults with unknown etiology conditions or suspected rare disease with multiple health concerns are increasingly asking for a comprehensive diagnostic molecular test as a first and not last test to quickly pave the way for their precise care.



Common challenges in daily practice include the limited number of genetic providers and clinics, small number of laboratories offering GS testing at an affordable self-pay cost, poor patient insurability, technical limitations including options for short and long read reanalysis, and lastly, practically no availability for the ordering clinical geneticist outside academic centers to reanalyze the GS data ad hoc.



We believe that reanalysis of inconclusive GS by the ordering provider can be a useful diagnostic tool and should be considered in the genetics training curriculum preparing future providers for the longitudinal genetic service across the lifespan.

Conclusion
In this small clinical cohort, we offered GS in 13.33% of our patients and identified a pathogenic gene variant in 33.33% of cases similarly to other cohorts. We also identified multiple carriers and pharmacogenetic results. GS is a once in a lifetime test offered to an increasing number of patients. In adults with complex or undiagnosed disease, GS could be a useful diagnostic tool as a first test in the clinic. Reanalysis of inconclusive genomic data by the ordering provider can be valuable in the long-term care, well-being of the patient, and the whole family.



References:

1. Psychogios A., Trachana K. eP219: Genome Sequencing (GS) as a first test in the clinic, https://www.sciencedirect.com/science/article/pii/S1098360022002726

2. Bagger, F.O.et al. Whole genome sequencing in clinical practice. BMC Med Genomics 17, 39 (2024). https://doi.org/10.1186/s12920-024-01795-w

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