Types of Genome Testing for Patients with Family History of Genetic Disorders or Unexplained Medical Conditions
For patients with a family history of genetic disorders or unexplained medical conditions, the recommended genomic testing approach follows a tiered strategy: start with targeted gene panel testing when a specific syndrome is suspected, escalate to whole exome sequencing (WES) when panel testing is negative or the phenotype is nonspecific, and reserve whole genome sequencing (WGS) for cases where WES fails to identify causative variants or when structural variants are suspected. 1, 2
Initial Testing Strategy: Targeted Gene Panels
Gene panel testing should be the first-line approach when clinical presentation suggests a specific genetic syndrome (e.g., cardiovascular conditions, neuromuscular disorders, or metabolic diseases). 1
For cardiovascular conditions like hypertrophic cardiomyopathy, panels focusing on 8 core sarcomere genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC1) identify disease-causing variants in approximately 30% of sporadic cases and 60% of familial cases. 1
For cardiac arrhythmias, targeted testing should focus on genes with definitive evidence: SCN5A alone for Brugada syndrome, and KCNQ1, KCNH2, and SCN5A for long-QT syndrome, as most other genes previously implicated lack sufficient evidence. 1
Expanding to larger multi-gene panels usually does not add diagnostic value and increases the likelihood of variants of uncertain significance (VUS), which complicate clinical management. 1
Escalation to Whole Exome Sequencing (WES)
WES should be performed when:
Targeted gene panel testing fails to identify a causative variant despite strong clinical suspicion. 1
The patient presents with a nonspecific constellation of findings that don't clearly point to a single syndrome (e.g., children with neurodevelopmental problems, congenital anomalies, and developmental abnormalities). 1
Multiple family members are affected but directed genetic testing has not identified a causal variant. 1
Very early onset inflammatory bowel disease (VEOIBD, defined as onset by age 6 years) or severe refractory disease suggests a monogenic disorder rather than typical polygenic disease. 1
A child has a severe phenotype with no family history, suggesting a de novo mutation. 1
Standard sequence analysis detects only one mutation in conditions requiring biallelic variants (e.g., only 94% of GSD Ia cases have both mutations identified by standard sequencing). 3
WES Technical Considerations
WES captures all protein-coding regions (exons) and can detect single-nucleotide variants, small insertions/deletions, and copy number variants. 4
Trio analysis (testing affected child plus both parents) enhances diagnostic yield by identifying de novo mutations and clarifying inheritance patterns. 1
WES must be performed in CLIA/CAP-certified laboratories with review by qualified clinical molecular geneticists. 4
Confirmation of relevant variants identified by WES should be performed using Sanger sequencing before clinical decisions are made. 4
Whole Genome Sequencing (WGS)
WGS should be reserved for cases where WES fails to identify causative variants, as it captures non-coding regulatory regions and structural variants that WES misses. 3, 2
WGS is particularly valuable for detecting complex structural variants or mutations in non-coding regions that affect gene expression. 4
WGS requires comprehensive computational infrastructure and specialized bioinformatics pipelines, producing approximately 5 million variants per analysis that require expert interpretation. 2
Cascade Testing After Positive Results
Once a pathogenic or likely pathogenic variant is identified in the proband:
First-degree relatives should undergo targeted cascade testing for the specific familial variant. 1
Family members who test negative for the familial variant can be released from lifelong clinical surveillance. 1
Family members who test positive require regular clinical screening at intervals determined by the specific condition. 1
This cascade approach is only beneficial for conditions where presymptomatic treatment can delay disease onset, reduce severity, prevent catastrophic events, or influence reproductive counseling. 1
Secondary Findings Considerations
When performing WES or WGS, laboratories should evaluate the 59 genes recommended by the American College of Medical Genetics and Genomics (ACMG) for actionable secondary findings, including 28 genes associated with cardiovascular conditions. 1
Patients must be counseled before testing about the possibility of secondary findings unrelated to their primary condition, and their preferences for receiving such information should be documented. 1
For pediatric testing, consider whether secondary findings provide actionable information in childhood versus predictive information that could be deferred until adulthood. 1
Critical Pitfalls to Avoid
Do not act on variants of uncertain significance (VUS). VUS results neither support nor refute genetic pathogenesis and should not guide clinical management. 1, 4
Variants should be periodically reevaluated every few years, as approximately 11% of variants are reclassified over 6 years, potentially changing cascade screening recommendations. 1
For patients with negative genetic testing, family members still require clinical screening at regular intervals because of considerable phenotypic heterogeneity in age of onset and disease progression. 1
Avoid genetic testing for late-onset disorders like Alzheimer's disease outside of research settings, as the clinical utility remains uncertain and testing may cause more harm than benefit. 1
Ensure proper genetic counseling accompanies all testing to help patients understand implications, including probabilistic nature of results and impact on family members. 5, 6
Special Populations
For patients with suspected familial hypercholesterolemia, inflammatory bowel disease with very early onset, or cardiac arrest survivors, genetic testing should be guided by specific clinical indices of suspicion rather than applied broadly. 1
Postmortem genetic testing using blood or tissue collected at autopsy can confirm diagnosis and enable cascade testing when the family variant is unknown and no other affected family members are living. 1