Clinical Genomics

Genomic Changes with Aging and Undiagnosed Diseases

• Analysis of genomic and physiological features in individuals over 70 using blood as a DNA source
• Findings include decline in mitochondrial number and Y-copy number in males, increase in somatic variant burden and clonal hematopoiesis
• Medical Genome Reference Bank contains whole genome and phenome data for 2,570 healthy elderly
• Undiagnosed diseases refer to conditions with no documented diagnosis, estimated at 7,000 diseases with an average 7.6 years for diagnosis in the US
• Genetic difficulty in determining diseases due to low frequency of mono-genetic diseases and complex heterozygote conditions
• Efforts to share phenomic and genomic data through consortia for better diagnosis using human phenotype ontology
• Diagnostic methods for undiagnosed diseases include karyotyping, chromosomal microarray, exome sequencing, and proteomics
• Combining biological knowledge from cell and animal models has improved diagnosis rates by about 10%
• Leveraging artificial intelligence and deep-learning for diagnosis through data synthesis and the development of Face2Gene
• DeCODE, an Iceland company, conducts several GWAS and trio/twin studies leveraging unique population genetics and social features
• Trio study on recombination frequency shows crossover hotspots, complex crossovers, and maternal age effects on crossover number
• Crossover results in de novo mutations, mostly in non-coding regions potentially modifying transcription of nearby coding genes

Integrating Genomic Medicine into Healthcare

• Genome Analytical/Diagnostic Methods include multiplex PCR panels for specific diseases and custom microarrays for genetic counseling or treatment.
• Targeted sequencing using phenomic linking is available at a cost of around $1,000 per person.
• Cascade (family) whole genome or exome sequencing allows for the identification of inheritance and recombination sites and can help in identifying candidate genes based on potential mode of transmittance.
• Insurance coverage for genomic sequencing in children and adults is a current challenge.
• Phenomic methods involve digitized patient data, patient interview/history, and the consolidation of data in digital format initiated by the Dept. of Health and Human Services.
• Most hospitals now use EHR for data entry and analysis for treatment, which allows for rapid communication and data mining when linked with genomic data.
• Clinical utility of genomic sequencing considerations include technical efficacy, diagnostic accuracy efficacy, and therapeutic efficacy.
• Current challenges in the use of EHR for genomic medicine involve a lack of standards to represent and communicate genomic information and the inability to store genomic information in current EHR systems.
• Integrating genomic medicine into primary care in Canada involves family physician questionnaires, which reveal a lack of confidence in genomic medicine skills needed for practice and cautious optimism about its clinical benefits.
• Family physicians in Canada see their role in developing family history/pedigrees, making referrals, and supporting patients with genetic diseases, but they need training and educational resources that can be integrated into primary care practice.
• Educational resources for primary care practice in genomic medicine should include case studies starting with the first presentation of the patient in the primary care setting.
• The study is authored by Dr. Darl Ray Swartz and published in npj Genomic Medicine (2020) and Frontiers in Genetics.