Table 1.
Patients with PAN with rare variants in ADA2 and/or reduced ADA-2 enzyme activity*
| Patient | Sex | Age at onset, years | Age at diagnosis, years | Age at study entry, years | Nucleotide change | Amino acid substitution | MAF | ACMG/AMP classification | ADA-2 activity, mU/ml (HPLC) |
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| 2VAR-1 | M | 22.8 | 22.9 | 24.7 | c.140G>C | p.G47A | 6.01−05 | LP (PM1, PM2, PM5, PP1, PP5) | NA |
| 2VAR-1 | M | 22.8 | 22.9 | 24.7 | c.316C>T | p.P106S | 1.99−05 | LP (PM1, PM2, PP3, PP5) | NA |
| 2VAR-2 | F | 16.4 | 17.4 | 18.9 | c.982G>A | p.E328K | – | LP (PM1, PM2, PM5, PP3, PP5) | 2.2 |
| 2VAR-2 | F | 16.4 | 17.4 | 18.9 | c.1065C>A | p.F355L | 2.34−04 | LP (PM1, PM2, PM3, PP5) | 2.2 |
| 2VAR-3 | M | 10.1 | 24.4 | 34.4 | c.1147G>A | p.G383S | 3.58−05 | LP (PM1, PM2, PP3, PP5) | 0.1 |
| 2VAR-3 | M | 10.1 | 24.4 | 34.4 | c.1147G>A | p.G383S | 3.58−05 | LP (PM1, PM2, PP3, PP5) | 0.1 |
| 2VAR-4 | M | NA | 15.1 | NA | c.139G>T | p.G47W | 3.98−06 | LP (PM1, PM2, PM5, PP3, PP5) | NA |
| 2VAR-4 | M | NA | 15.1 | NA | c.506G>A | p.R169Q | 4.74−04 | P (PS3, PM2, PM3, PP1, PP3) | NA |
| 1VAR-1 | F | 34.4 | 34.4 | 34.4 | c.100C>T | p.R34W | 7.78−05 | LP (PM1, PM2, PM3) | NA |
| 1VAR-2 | F | 62.0 | 62.1 | 66.1 | c.194C>T | p.T65M | 6.29−04 | VUS (PM1, PM2) | 22.7 |
| 1VAR-3 | M | 10.6 | 10.6 | 17.8 | c.927G>A | p.M309I | 1.67−03 | VUS (PM2, BS1, BP6) | NA |
| 1VAR-4 | F | 49.5 | 49.6 | 53.4 | c.1045G>A | p.V349I | 2.14−03 | VUS (PM1, PM2, BP4, BP6) | 14.9 |
| 1VAR-5 | M | 48.4 | 48.4 | 48.5 | c.1358A>G | p.Y453C | 8.84−05 | LP (PM1, PM2, PP3, PP5) | 11 |
| 0VAR-1 | M | 59.3 | 60.3 | 60.9 | 3.3 | ||||
| 0VAR-2 | M | 50.3 | 51.3 | 54.2 | 6.4 | ||||
| 0VAR-3 | F | 65.3 | 65.6 | 71.2 | 6.8 | ||||
| 0VAR-4 | M | 63.3 | 64.2 | 71.6 | 7.5 | ||||
| 0VAR-5 | M | 49.0 | 49.0 | 50.8 | 8.3 | ||||
| 0VAR-6 | M | NA | 36.7 | 42.0 | 8.9 | ||||
For each of the patients with rare variants (VAR) in ADA2, sex, age at onset of symptoms, age at diagnosis of polyarteritis nodosa (PAN), and age at study entry are shown. For each of the identified variants, change in the coding sequence (nucleotide change), protein change (amino acid substitution), minor allele frequency (MAF) as reported in the Genome Aggregation Database, and the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) classification analysis are shown. Adenosine deaminase 2 (ADA-2) activity in available serum samples was measured using a high-performance liquid chromatography (HPLC)–based method. For patients with reduced ADA-2 enzymatic activity without detectable variants, information on sex, age at onset of symptoms, age at diagnosis of PAN, age at study entry, and ADA-2 activity is shown. LP = likely pathogenic; PM = pathogenic moderate; PP = pathogenic supporting; NA = not available; P = pathogenic; PS = pathogenic strong; VUS = variant of uncertain significance; BS = benign strong; BP = benign supporting. For variant classification and for definition of PM1, PM2, PP3, PP5, BS1, BP4, and BP6, see Supplementary Methods, http://onlinelibrary.wiley.com/doi/10.1002/art.41549/abstract. Reference values are as follows: deficiency of ADA-2 patients (n = 55), mean ± SD 0.4 ± 0.5 mU/ml (range 0–2.5); ADA-2 carriers (n = 46), mean ± SD 5.7 ± 1.9 mU/ml (range 2.9–11.4); healthy controls (n = 27 + pooled human plasma), mean ± SD 13.0 ± 5.1 mU/ml (range 4.7–27.2).