Evolving health care through personal genomics

Abstract

With the rapid evolution of next-generation DNA sequencing technologies, the cost of sequencing a human genome has plummeted, and genomics has started to pervade health care across all stages of life - from preconception to adult medicine. Challenges to fully embracing genomics in a clinical setting remain, but some approaches are starting to overcome these barriers, such as community-driven data sharing to improve the accuracy and efficiency of applying genomics to patient care.

Figure 1. The use of genomics throughout an individual’s lifespan.

Case studies of the use of genomics to inform patient care at different stages of life. Case Example 1 - Preconception testing Bob and Julie are considering having a child and seek preconception genetic testing. Julie is found to carry seven pathogenic variants for recessive diseases and Bob is found to carry five. There is one gene, SMN1, for which both are carriers. This puts the couple at a 25% risk of having a child with spinal muscular atrophy, a progressive muscle-wasting disease. Julie and Bob decide to pursue preimplantation genetic diagnosis to avoid a pregnancy with an affected fetus by selecting embryos that do not inherit both pathogenic variants. Case Example 2 - Prenatal testing Sofia is pregnant with her first child. Wanting to do everything to ensure a healthy newborn, she opts for whole-exome sequencing. The sequencing results identify pathogenic variants in the PKU gene, which have been associated with phenylketonuria. Armed with this information, Sofia immediately begins a low-phenylalanine diet during pregnancy and arranges for the availability of a special dietary infant formula to avoid neonatal exposure to phenylalanine. With this treatment plan, the baby is expected to develop normally and lead a productive adult life. Case Example 3 – Newborn screening and paediatric care Mei has just given birth to a healthy baby girl. She decides to have her daughter’s genome assessed using exome sequencing. This test reveals two pathogenic variants in the GJB2 gene, putting the newborn at risk of hearing loss that can be progressive. Although the child passed a newborn hearing screening, a diagnostic audiological test reveals mild hearing loss, often missed in newborn screening. The baby is fitted with hearing aids to allow for normal auditory development. The baby’s hearing is monitored yearly and if it progresses to profound deafness, the option for cochlear implantation surgery can be offered to the family. Case Example 4 – Adult medicine Joseph was interested in pursuing genomic sequencing to learn about his own health risks. He ordered a whole-genome sequencing test through a medical geneticist offering concierge services and discovered that he harbours a pathogenic variant for hypertrophic cardiomyopathy. This finding prompted a cardiac evaluation which revealed normal cardiac morphology and conduction systems; however, a detailed family history assessment identified suspicion for hereditary sudden cardiac death on his mother’s side based on unexplained drowning of a sibling and two maternal uncles who died of heart attacks at age 55 and 60 years. Given the incomplete penetrance of hypertrophic cardiomyopathy, Joseph’s actual risk of disease is unclear, but with a positive at-risk genotype, he will pursue regular cardiac evaluations and inform family members of their possible risk. Case Example 5 – Access to shared resources to support patient care Jessica is seeing a genetic counsellor (GC) to discuss her risk of breast cancer after her grandmother and aunt died of breast cancer and her mother was recently diagnosed. She brings a copy of her aunt’s laboratory report from 2008 that notes a pathogenic variant identified and references a publication to support the variant interpretation. Jessica’s GC quickly looks up the variant in ClinVar and discovers that five clinical laboratories now interpret the variant as benign citing more recent evidence accumulated from clinical testing. The GC suggests that her aunt’s testing probably did not identify the correct cause of disease in her family and suggests Jessica’s mother have testing to identify another potential cause of hereditary breast cancer that may not have been examined in 2008. If a cause of breast cancer is found in her mother, Jessica would be able to pursue testing to inform her own risk. Case Example 6 – Elderly health John had watched his father suffer a long end-of-life battle with Alzheimer disease. Curious about his own risks, he elected to obtain genetic testing through a direct-to-consumer testing company and learned that he harbours two copies of the APOE ɛ4 variant, putting him at heightened risk of Alzheimer disease. He also learned that his ancestral origins were more diverse than he had realized previously and was able to connect with several distant relatives though an online ancestry portal.

Figure 2. Detection rates across a selection of molecular diagnostic tests.

These data are from multiple studies spanning several indications[–51]. The specific detection rate can vary based upon the specificity of the clinical presentations and the comprehensiveness of the test panel.

Figure 3. Centralized and federated databases.

In a centralized database model, submitters send data to a single central database. In a federated system, data remains in the originating database with queries supported through application programming interfaces (APIs).

Figure 4. Penetrance of genetic disorders.

The penetrance of a selection of well-known genetic disorders is shown[–77]. The midpoint was used for data expressed as a range.