Genetic Testing in Amyloidosis
When to Perform Genetic Testing
Genetic testing with TTR gene sequencing is recommended for all patients diagnosed with transthyretin cardiac amyloidosis to differentiate hereditary variant (ATTRv) from wild-type (ATTRwt) disease. 1 This distinction is critical because it determines prognosis, guides treatment decisions including liver transplantation eligibility, and identifies the need for family screening. 2
Clinical Scenarios Requiring Genetic Testing
Confirmed ATTR amyloidosis: After diagnosis via bone scintigraphy (99mTc-PYP) in patients without monoclonal light chains, TTR gene sequencing must be performed. 1, 3
All suspected hereditary amyloidosis: Genetic testing should be performed in African-Americans and patients presenting with peripheral neuropathy, as these populations have higher prevalence of specific TTR mutations (particularly V122I variant). 1
Biopsy-proven ATTR cases: Even when liquid chromatography tandem mass spectrometry (LC-MS/MS) identifies ATTR, genetic testing remains essential because LC-MS/MS fails to detect mutations in 16% of cases, particularly homozygous V122I mutations and variants like A19D, F44L, T60A, and I68L. 2
Apparent AL amyloidosis without clear confirmation: In patients with suspected AL amyloidosis where confirmation cannot be obtained, genetic testing should be pursued as 9.7% of such cases are actually hereditary amyloidosis (most commonly fibrinogen A alpha-chain and transthyretin mutations). 4
Family Screening Protocol
All first-degree relatives of patients with confirmed hereditary transthyretin amyloidosis (ATTRv) should undergo genetic screening with TTR gene sequencing. 5 Extended biologically related relatives may also be considered. 5
Key Restrictions and Timing
Do not offer genetic testing to minors, but testing can be offered to young adults when results guide lifestyle choices or reproductive planning. 5
For AL amyloidosis families, genetic screening is not indicated as this form is not hereditary. 5
Surveillance for Asymptomatic Carriers
Begin surveillance approximately 10 years before the age of disease onset observed in affected family members. 5
Start surveillance immediately if any symptoms compatible with amyloidosis develop, regardless of predicted onset age. 5
Annual assessments should include: ECG, echocardiogram with strain imaging, cardiac biomarkers (NT-proBNP), and targeted neurologic examination. 5
In-depth assessments every 3-5 years should include: bone scintigraphy, cardiac MRI with late gadolinium enhancement, and comprehensive neurologic assessments if symptoms present. 5
Red Flags Requiring Immediate Genetic Evaluation
Left ventricular wall thickness ≥14 mm with fatigue, dyspnea, or edema, especially with discordance between echocardiographic wall thickness and QRS voltage on ECG. 1, 5
Bilateral carpal tunnel syndrome in the context of cardiac symptoms. 5
Concomitant conditions: Aortic stenosis, HFpEF, lumbar stenosis, or autonomic/sensory polyneuropathy. 1, 3
Critical Diagnostic Pitfalls
The presence of low-grade monoclonal gammopathy (detected in 24% of hereditary amyloidosis patients) can lead to misdiagnosis as AL amyloidosis. 4 This underscores why genetic testing cannot be bypassed even when monoclonal proteins are present.
LC-MS/MS proteomics alone is insufficient to rule out pathogenic mutations, as it fails to identify mutations in 16% of ATTR cases, particularly homozygous mutations and certain variants. 2 Therefore, genetic testing should be performed in most cases of ATTR amyloidosis regardless of proteomics results.
Genetic Counseling Requirements
Provide genetic counseling before and after testing to all patients and at-risk family members. 5
Establish long-term therapeutic alliance with mutation carriers for ongoing monitoring and psychological support throughout the screening process. 5
Genetic test results should be communicated by physicians skilled in hereditary amyloidosis or expert geneticists, not sent directly to patients. 1
Impact on Treatment Decisions
Correct identification of hereditary ATTR amyloidosis is essential for:
- Estimating prognosis (ATTRv typically has earlier onset and different progression than ATTRwt). 2
- Guiding use of liver transplantation, which is only appropriate for hereditary forms. 2
- Enabling family counseling and cascade screening. 2, 6
- Determining eligibility for tafamidis therapy, which is indicated for both wild-type and variant transthyretin cardiac amyloidosis with NYHA class I-III symptoms. 1, 3