Alpha-1 Antitrypsin Deficiency — a common genetic cause of early-onset emphysema and liver disease that goes undiagnosed for an average of 7 years after symptom onset.
Whole genome sequencing reads the complete SERPINA1 gene, identifying all Pi alleles — including rare compound heterozygous combinations — to establish full genotype and predict pulmonary and hepatic disease risk.
Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant disorder caused by pathogenic variants in SERPINA1, the gene encoding alpha-1 antitrypsin (AAT) — a serine protease inhibitor produced primarily in hepatocytes that protects lung parenchyma from neutrophil elastase-mediated destruction. AATD is estimated to affect 1 in 2,500 individuals of European ancestry and approximately 3.4 million people worldwide, making it one of the most common serious monogenic disorders — yet it remains chronically and severely underdiagnosed. Median time from first respiratory symptoms to diagnosis is 7-8 years, during which irreversible lung damage accumulates.
SERPINA1 alleles are designated by the Pi (protease inhibitor) nomenclature. The normal allele is Pi*M. The most clinically significant variants are Pi*Z (p.Glu342Lys; rs28929474) and Pi*S (p.Glu264Val; rs17580). Pi*ZZ homozygotes — the most severely affected genotype — have AAT serum levels approximately 15% of normal, due to both reduced secretion and intrahepatic polymerization of the misfolded Z protein. Pi*SZ compound heterozygotes have AAT levels approximately 40% of normal and face elevated but lower lung disease risk. The polymerizing Z protein accumulates in hepatocytes, causing progressive liver disease (cirrhosis, hepatocellular carcinoma) in a subset of Pi*ZZ individuals through a distinct toxic gain-of-function mechanism independent of the lung disease pathway.
Augmentation therapy with intravenous alpha-1 proteinase inhibitor (Prolastin, Zemaira, Aralast) slows emphysema progression in Pi*ZZ patients with established airflow obstruction — the only condition-specific approved treatment. Survival benefit is most pronounced when therapy begins before significant lung destruction. Smoking accelerates AATD lung disease dramatically; Pi*ZZ smokers lose lung function 3-4 times faster than non-smokers with AATD. Early diagnosis enables smoking cessation counseling before irreversible damage, avoidance of occupational dust and fume exposure, and initiation of augmentation therapy at the optimal stage of disease.
More than 120 SERPINA1 variants have been described. Rare alleles (Pi*I, Pi*F, Pi*P, Pi*Null) produce a spectrum of AAT deficiency phenotypes from intermediate deficiency to complete absence of secreted protein.
Standard AATD testing checks Z and S alleles in isolation. Complete SERPINA1 genotyping requires resolving the full allelic architecture — including rare alleles that determine whether a patient has AATD or simply carries one deficiency allele.
Pi*SZ compound heterozygotes are frequently missed by binary Z/S tests
Point-of-care and standard laboratory AATD screening tests are optimized to detect the Z allele (Pi*Z) and report Pi*MZ or Pi*ZZ genotypes. Compound heterozygous Pi*SZ — which carries meaningful lung disease risk and is present in approximately 1 in 625 people of European ancestry — requires simultaneous characterization of both the Z and S alleles. Rare SERPINA1 variants not included in limited panels produce Pi*MZ-equivalent or Pi*ZZ-equivalent AAT levels in patients who test 'normal' by Z-allele-only screens. Complete SERPINA1 genotyping by whole genome sequencing identifies all alleles simultaneously, including rare compound heterozygous combinations that appear normal on binary testing.
Distinguishing Pi*MZ from Pi*ZZ determines augmentation therapy eligibility
NICE, ERS, and ATS guidelines recommend AAT augmentation therapy for Pi*ZZ and Pi*null patients with established obstructive lung disease — not for Pi*MZ carriers. The clinical and financial implications of this genotype distinction are significant: augmentation therapy costs approximately $50,000-100,000 per year. Accurate genotyping distinguishes patients who qualify for augmentation from carriers who require only surveillance and risk-factor counseling. Without complete SERPINA1 genotyping, a Pi*SZ patient with a very low measured AAT level might be classified incorrectly as Pi*MZ and denied appropriate treatment — or conversely, a Pi*MZ carrier with co-existing COPD might be prescribed augmentation that AATD guidelines do not support.
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A patient had spent decades in the UK healthcare system without a diagnosis. Dante data, accepted by NHS clinical teams at Queen Elizabeth University Hospital Glasgow, identified Noonan Syndrome and a RUNX1 leukemia-associated variant that had gone undetected. After 40 years, they finally had an answer.
A complete read delivers a complete picture.
A patient came to Dante to investigate periodic paralysis. Reading the complete genome identified a concurrent hereditary cardiac finding — Brugada syndrome — that their doctor confirmed with an ECG. The result also explained a family member's unresolved cardiac history. One test. Every answer in it.
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Jennifer sequenced her genome with Dante two years before her breast cancer diagnosis. When treatment began, Dante's pharmacogenomics data showed her prescribed chemotherapy would cause serious adverse effects. Her doctor selected an alternative — and she started effective treatment from day one.
Every genetic question deserves a complete answer.
Whether you are searching for answers today or protecting your health for tomorrow, a complete read of your entire genome is the only place to start.
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Your genome contains inherited variants associated with medical conditions like cardiac, cancer, and neurological. We read all of them — with the clinical depth to give the result meaning.
Learn more →When traditional lab tests say you're fine. And you know you're not.
Standard diagnostic tests check for a pre-selected set of answers. We sequence your full DNA — including parts that no test was designed to check. If the answer is in your genome, we will help you find it.
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Your genes determine which treatments are most likely to work — and which are not. We give your doctor the tools and insights to inform your treatment plan.
Learn more →You want to know before something forces the question.
Some people don't wait for a diagnosis or a family history to act. Whole genome sequencing gives you the complete genetic picture now — so you and your doctor can make informed decisions before anything becomes urgent.
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Common questions about whole genome sequencing.
What is the difference between whole genome sequencing and a targeted genetic test?
Targeted genetic tests — including standard hereditary cancer panels — read a pre-defined list of known variants in a specific set of genes. They are designed to find what they already know to look for. Whole genome sequencing reads your entire genome: all 6 billion base pairs, every gene, every region between genes. A Mayo Clinic study published in JAMA Oncology found that standard testing guidelines missed more than half of patients with inherited cancer mutations. Genome Test does not have a fixed list.
What will I receive when my results are ready?
Your Dante Genome delivers 200+ physician-ready reports organized by clinical category — hereditary cancer, cardiac conditions, rare diseases, pharmacogenomics, carrier status, and more. Reports are delivered to your secure Genome Manager and are formatted for direct clinical use. Your genome data is permanently retained and re-analyzed automatically as science advances.
What happens if a clinically significant variant is found?
If a pathogenic or likely-pathogenic variant is identified, it will be clearly flagged in your physician-ready report with clinical context, published evidence, and recommended next steps. We recommend sharing any clinically significant finding with your physician or a genetic counselor, who can guide decisions about surveillance, risk reduction, or cascade testing for family members.
How is this different from a consumer DNA test like 23andMe or AncestryDNA?
Consumer DNA tests use genotyping chips that read less than 0.1% of your genome — a tiny pre-selected set of common variants. They are optimized for ancestry and population-level traits, not clinical genetic findings. The Dante Genome Test sequences 100% of your genome at 30X coverage, the same standard used in clinical diagnostic settings. The two tests are not comparable in scope, methodology, or clinical utility.
How long does it take to get results, and how are they delivered?
Your collection kit ships within 48 hours of ordering. Once your sample arrives at our CLIA-certified laboratory, sequencing and analysis takes 6–8 weeks. Results are delivered securely to your Genome Manager, where you can access your reports, share them with your physician, and receive automatic updates as new findings are validated against your genome.
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Dante Labs works with patient advocacy groups of any size — for Alpha-1 Antitrypsin Deficiency and other conditions, rare and common. We support groups in any country, including virtual patient advocacy groups.
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Ships within 48 hours · Results in 6–8 weeks
