How can I arrange appropriate genetic testing for a patient with a suspected hereditary disease?

How to Arrange Genetic Testing for a Patient with Suspected Hereditary Disease

Refer the patient to a genetic counselor or medical geneticist early in the evaluation process, as they should be involved when genetic testing is offered and when results are disclosed 1.

Step 1: Determine if Genetic Referral is Indicated

Before ordering any testing, assess whether the patient meets criteria for genetic evaluation based on their clinical presentation 1:

For Adult Patients - Personal History Red Flags:

• Abnormal sexual maturation or delayed puberty (to rule out chromosomal abnormalities like Klinefelter syndrome) 1
• More than 2 recurrent pregnancy losses (chromosomal rearrangements cause 5-7% of cases) 1
• Unexplained tall or short stature for genetic background 1
• One or more birth defects 1
• Six or more café-au-lait macules ≥1.5 cm (neurofibromatosis type 1) 1
• Statin-induced myopathy (mitochondrial disorder) 1

For Personal or Family History:

• Cancer with compelling family history, young age at onset, bilateral lesions, or familial clustering (BRCA1/2, Lynch syndrome, FAP) 1
• Cardiovascular problems like cardiomyopathy, long QT syndrome, or hyperlipidemia 1
• Connective tissue disorders (Ehlers-Danlos, Marfan syndrome) 1
• Excessive bleeding or clotting disorders 1
• Progressive neurologic conditions (peripheral neuropathy, myopathy, ataxia, early-onset dementia) 1
• Early-onset hearing or vision loss 1

For Neonates and Children:

• Abnormal newborn screening test 1
• Congenital hypotonia or hypertonia 1
• Unexplained intrauterine growth retardation 1
• Dysmorphic features with developmental delay 1

Step 2: Perform Pre-Test Evaluation

Complete a focused three-generation family history with pedigree analysis documenting specific conditions, ages of onset, consanguinity, and ethnic background 2, 3. This is essential before ordering any genetic testing 3.

Conduct a genetics-focused physical examination looking for dysmorphic features, growth parameters, skin findings (such as café-au-lait spots), and organ system anomalies 2, 3.

Step 3: Select the Appropriate Testing Strategy

When a Specific Syndrome is Clinically Suspected:

Order targeted single-gene or limited gene panel testing first when the clinical presentation strongly suggests a specific diagnosis 3. For example:

• For hereditary breast/ovarian cancer in Ashkenazi Jewish patients: Test for the 3 founder mutations first (BRCA1 185delAG, 5382insC, and BRCA2 6174delT), then consider full sequencing if negative and other criteria are met 1
• For pheochromocytoma/paraganglioma: DNA sequencing and deletion testing are obligatory for FH, NF1, RET, SDHB, SDHD, VHL, and possibly MEN1 1

When the Phenotype Suggests Genetic Heterogeneity:

Consider comprehensive genomic panels (exome or genome sequencing) as first- or second-tier testing for patients with 3:

• Unexplained developmental delay or intellectual disability
• Congenital anomalies without a clear syndromic diagnosis
• Complex rare conditions when targeted testing is non-diagnostic
• Parental consanguinity (increases likelihood of autosomal recessive conditions)

Understand the trade-offs: Smaller focused panels offer higher specificity with fewer variants of uncertain significance, while larger panels provide higher sensitivity when family history is incomplete 3.

Step 4: Obtain Informed Consent

Provide comprehensive genetic counseling before testing to ensure the patient understands 4, 5:

• The purpose and limitations of the test
• Possible results (positive, negative, variant of uncertain significance)
• Implications for the patient and family members
• Potential psychological, social, and insurance implications
• The option to decline testing

For comprehensive genomic panels, discuss secondary findings: The American College of Medical Genetics and Genomics recommends reporting pathogenic variants in 59 medically actionable genes regardless of the primary indication 3.

Step 5: Coordinate Testing Through Appropriate Channels

If a known familial mutation exists: Test the patient for that specific mutation first 1. This is more cost-effective and provides clearer interpretation.

If no affected family member is available for testing: Consider testing unaffected family members, but discuss significant limitations in interpreting results 1. Testing paraffin-derived DNA from deceased relatives may be an option if DNA is obtainable 1.

For certain conditions like pheochromocytoma/paraganglioma: Genetic testing is recommended for all patients regardless of age at presentation and family history 1.

Step 6: Interpret Results and Manage Follow-Up

If a Deleterious Mutation is Found:

• Implement syndrome-specific surveillance and management protocols 1
• Offer cascade testing to first-degree relatives in all hereditary conditions 1
• For conditions with imprinting (like SDHD): Test second-degree relatives as well 1

If a Variant of Uncertain Significance is Found:

• Do not use for clinical decision-making 1
• Consider referral to research studies that aim to define the functional impact of the variant 1
• Offer individualized recommendations, such as testing the next family member with highest likelihood of carrying a pathogenic variant 1

If Testing is Negative:

• Consider periodic reanalysis of negative comprehensive genomic panel results, as this improves diagnostic yield by 4-10% as new genes are discovered and variant interpretation improves 3
• Reassess clinical diagnosis and consider alternative testing strategies

Critical Pitfalls to Avoid

Do not order comprehensive genomic panels when a specific syndrome is clinically diagnosed and targeted testing is more sensitive 3. This wastes resources and increases the likelihood of incidental findings.

Do not use genetic testing for general screening in patients lacking clinical features or family history suggesting genetic etiology 3.

Do not order all possible genetic tests simultaneously without a stepwise approach guided by clinical presentation 1.

Do not forget to inform relatives: When a patient is found to be a carrier, encourage them to inform relatives of the risk and availability of carrier screening 6.

Ensure proper qualifications: Clinicians ordering comprehensive genomic panels must demonstrate competence in performing basic clinical genetics evaluation and determining test appropriateness 3.