Alpha-1 Antitrypsin Deficiency as an Incidental Finding in Clinical Genetic Testing

To the Editor:

Sequencing of gene panels or whole exomes has become increasingly common for the diagnosis and management of genetic disorders. These tests frequently uncover variants in genes unrelated to the clinical condition, termed “incidental” or “secondary” findings. An additional and rapidly growing source of incidental findings is direct-to-consumer genetic testing. Many of the variants discovered will be of uncertain clinical significance (1). However, there is potential to find variants with severe adverse health effects. The American College of Medical Genetics published recommendations for reporting secondary findings, including a limited list of disease genes, with periodic updates (2). However, this list does not include cystic fibrosis or alpha-1 antitrypsin deficiency (AATD), two relatively common genetic disorders encountered by specialists in pulmonary medicine.

AATD is associated with a greatly increased risk for emphysema and, less so, bronchiectasis, in adults. Liver disease may present in childhood or adulthood. Alpha-1 antitrypsin is encoded by the gene SERPINA1 on chromosome 14. AATD-related lung disease follows an autosomal recessive inheritance pattern. Severe AATD is usually caused by two copies of the protease inhibitor (PI)*Z allele of the SERPINA1 gene (PI*ZZ genotype). AATD is one of the most common genetic conditions in the United States, with an estimated prevalence of 1 in 3,000 to 1 in 5,000 (3). Studies have identified multiple rare null alleles that yield no detectable serum protein (4). These would be expected to increase risk of lung disease but not liver disease. Compound heterozygosity for the PI*SZ genotype is an established risk factor for chronic obstructive pulmonary disease (COPD) (5). Heterozygous carriers of the PI*Z allele (PI*MZ) have an increased risk of airflow obstruction, especially in cigarette smokers (6), although not to the same degree as PI*ZZ individuals.

Herein, we describe three patients with AATD detected incidentally through different genetic tests, including the discovery of a novel null allele. This study was approved by the institutional review board at Partners Healthcare.

Case 1 is a 45-year-old nonsmoking male physician who underwent exome sequencing as a commercial promotion, revealing PI*SZ genotype (Table 1). He denied symptoms of lung or liver disease. He has a great uncle with COPD, who had not been tested for AATD. Pulmonary function tests (PFTs) and liver function tests were normal.

Table 1.

Two Individuals with Alpha-1 Antitrypsin Deficiency Incidentally Discovered through Genetic Sequencing

	Case 1	Case 2
Age, yr	45	32
Sex	Male	Male
Alpha-1 antitrypsin genotype	PI*SZ	PI*Z-Null†
Alpha-1 antitrypsin level, μM	9.2	4.8
Alpha-1 antitrypsin level, mg/dl	48	25
FEV1, L (% predicted)	4.68 (112)	5.21 (104)
FVC, L (% predicted)	6.08 (117)	6.27 (100)
FEV1/FVC ratio	0.77	0.83
Total lung capacity, L (% predicted)	7.49 (104)	6.77 (82)
DlCO, ml/min/mm Hg (% predicted)	29.6 (90)	38.4 (97)

^†Sequencing showed SERPINA1 heterozygosity, with one PI*Z allele and a complex frameshift mutation, g.94378591_94378598delGCAGCTTCinsTGTTTTT (NC_000014.9), between amino acid positions Glu346 and Ala348. This mutation leads to a premature stop codon at amino acid position 353, leading to a null allele, confirmed by isoelectric focusing of serum, which showed only Pi Z protein. This null allele had not been previously described and has been reported to the National Center for Biotechnology Information dbSNP database as rs864622043.

Case 2 is a 32-year-old male nonsmoker of Ashkenazi Jewish ancestry, with no symptoms or family history of lung or liver disease. During preconception counseling after his wife was found to be a carrier for an unrelated condition, he underwent clinical sequencing of a multigene panel. Sequencing showed one PI*Z allele and a complex frameshift mutation leading to a novel null allele (Table 1). PFTs and liver function tests were normal.

Case 3 is a 49-year-old nonsmoking adopted woman with a history of recurrent respiratory illnesses and mild exertional dyspnea; she was diagnosed with “asthmatic bronchitis” in her 20s. She was curious about her birth parents and purchased a direct-to-consumer genetic testing kit, revealing PI*ZZ genotype. Because she was generally feeling well, she took no action. Two years later, after meeting an individual with AATD, she underwent clinical testing (Table 2). PFTs showed mild airflow obstruction and a reduced Dl_CO. Chest computed tomography (CT) scan revealed mild bilateral lower lobe bronchiectasis.

Table 2.

Index Case with Alpha-1 Antitrypsin Deficiency Incidentally Discovered by Direct-to-Consumer Genetic Testing, and Her Two Sisters

	Case 3	Sibling 1	Sibling 2
Age, yr	49	45	50
Sex	Female	Female	Female
Alpha-1 antitrypsin genotype	PI*ZZ	PI*ZZ	PI*ZZ
Alpha-1 antitrypsin level, μM	6.3	6.3	6.9
Alpha-1 antitrypsin level, mg/dl	33	33	36
FEV1, L (% predicted)	3.38 (90)	3.61 (107)	3.0 (101)
FVC, L (% predicted)	5.01 (104)	5.26 (126)	3.9 (106)
FEV1/FVC ratio	0.67	0.69	0.77
Total lung capacity, L (% predicted)	7.49 (109)	7.23 (121)	7.7 (141)
DlCO, ml/min/mm Hg (% predicted)	20.4 (60)	24.5 (80)	19.8 (71)

She petitioned to have her birth records unsealed and found her birth mother and other blood relatives, many of whom were subsequently tested. Her two sisters were both found to have severe AATD. Her birth father (deceased) had a history of lung disease but had never been tested. Sister 1 is a 45-year-old nonsmoker with a mild productive cough and annual episodes of bronchitis. Chest CT scan revealed a few small bullae in the left lower lobe. Sister 2 is a 50-year-old nonsmoker. She had pneumonia at age 6 months. She has a history of recurrent respiratory illnesses during the winter and a minimally productive cough. She had wheezing and was diagnosed with asthma at age 45.

We describe three index cases with AATD discovered incidentally through different genetic testing methods. Two cases were asymptomatic with no evidence of organ dysfunction, but the third case and her two sisters had symptomatic respiratory disease.

Given the relatively common frequency of AATD, there will continue to be many individuals with incidental diagnoses made through clinical or direct-to-consumer genetic testing. Even without symptoms, these individuals may present to primary care providers and pulmonary specialists. Therefore, it is important for clinicians to be familiar with AATD. Early identification of AATD is important, because interventions such as smoking cessation and intravenous augmentation therapy can limit emphysema progression (7). Although not on the panel of genes defined by the American College of Medical Genetics, we contend that the finding of AATD is a medically actionable result.

Recently, the Alpha-1 Foundation (8) and the European Respiratory Society (9) have each published clinical practice guidelines for AATD, with both recommending an initial baseline lung function evaluation that includes measurement of diffusing capacity. Although more sensitive for the detection of emphysema and bronchiectasis, the role for chest CT scans in the evaluation of the patient with AATD is not as clear (10). Laboratory and ultrasound testing for cirrhosis and hepatocellular carcinoma is recommended. Patients should be advised to avoid cigarette smoking and hepatotoxins. Genetic counseling and testing of at-risk family members is important. The European Respiratory Society document recommends that patients with AATD be managed in specialized centers and includes a table of centers in Europe (9). The Alpha-1 Foundation maintains a similar list of U.S. centers that can be accessed at www.alpha1.org/Alphas-Friends-Family/Resources/Find-an-Alpha-1-Specialist.