Table 1. Germline Mutations in the SDHA, TMEM127, MAX, and SDHAF2 Genes and Corresponding Phenotypes in 64 Unrelated Index Patientsa.
| Germline Mutation, No. of Probands With Same Mutation/Nationality | Age at Diagnosis, y | Sex | Family History | Paraganglionic Phenotype | No. of Clinical Variables Suggesting Heritabilityb | Nucleotide Change | ACMG Variant Classc |
|---|---|---|---|---|---|---|---|
| SDHA | |||||||
| 1/Germany | 66 | M | Negative | Extra-adrenal, thoracic | 1 | c.1A>C | 5 |
| 1/Germany | 30 | M | Negative | Adrenal, unilateral | 1 | c.1A>T | 5 |
| 1/Germany | 27 | F | Negative | Carotid | 2 | c.2T>G | 5 |
| 1/Germany | 34 | M | Negative | Adrenal, unilateral | 1 | c.3G>C | 5 |
| 5/Germany | 15-37 | M and F | Negative and positive | Adrenal, unilateral; extra-adrenal, retroperitoneal; carotid; and jugular | 1-3 | c.91C>T | 5 |
| 2/Sweden | 20 and 47 | M and F | Negative | Extra-adrenal, retroperitoneal; adrenal, unilateral | 0-2 | c.223C>T | 5 |
| 1/Germany | 47 | F | Negative | Jugular | 1 | c.296A>G | 5 |
| 1/Germany | 26 | F | Negative | Jugular | 2 | c.457-1G>A | 5 |
| 1/Turkey | 17 | M | Negative | Extra-adrenal, retroperitoneal | 2 | c.566G>A | 4 |
| 1/Germany | 43 | M | Negative | Carotid | 1 | c.622T>C | 4 |
| 1/Sweden | 64 | M | Negative | Adrenal, unilateral | 0 | c.629G>A | 3 |
| 1/Germany | 53 | M | Negative | Jugular | 1 | c.778G>A | 4 |
| 1/United States | 33 | M | Negative | Extra-adrenal, pelvic | 2 | c.820G>A | 5 |
| 1/Poland | 27 | F | Negative | Adrenal, unilateral | 1 | c.830C>T | 3 |
| 1/Germany | 46 | F | Negative | Jugular | 1 | c.940G>A | 4 |
| 1/Germany | 24 | M | Negative | Adrenal, unilateral | 1 | c.1115C>G | 3 |
| 1/Germany | 63 | F | Negative | Carotid | 1 | c.1177G>A | 3 |
| 1/Germany | 58 | M | Negative | Adrenal, bilateral | 2 | c.1283_1298del | 5 |
| 1/United States | 30 | F | Negative | Extra-adrenal, pelvic | 2 | c.1316G>A | 4 |
| 1/Germany | 20 | F | Negative | Jugular | 2 | c.1334C>T | 5 |
| 1/Germany | 48 | M | Negative | Carotid, bilateral | 1 | C.1340A>G | 5 |
| 2/Germany and United States | 28 and 49 | M | Negative | Jugular; adrenal, unilateral, malignant | 1 | c.1361C>A | 4 |
| 1/Germany | 44 | M | Negative | Extra-adrenal, retroperitoneal | 1 | c.1432_1432 + 1del | 5 |
| 1/Germany | 50 | F | Negative | Jugular | 1 | c.1766G>A | 5 |
| 3/Germany, United States, and Turkey | 42-65 | M and F | Negative | Extra-adrenal, retroperitoneal, multiple; carotid; and vagal | 1-2 | c.1799G>A | 4 |
| 1/Poland | 39 | M | Negative | Adrenal, unilateral | 1 | c.1979C>G | 3 |
| TMEM127 | |||||||
| 4/United States and Germany | 35-58 | M and F | Negative and positive | Adrenal, unilateral | 0-1 | c.3G>A | 5 |
| 1/Germany | 68 | M | Negative | Adrenal, unilateral | 0 | c.73A>T | 5 |
| 1/Poland | 43 | F | Negative | Adrenal, bilateral | 1 | c.131T>G | 4 |
| 1/Germany | 58 | F | Negative | Adrenal, unilateral | 0 | c.215T>A | 5 |
| 1/Germany | 34 | F | Negative | Carotid | 2 | c.325T>C | 4 |
| 1/Germany | 45 | M | Negative | Adrenal, bilateral | 1 | c.410-1G>C | 5 |
| 1/Germany | 66 | M | Negative | Extra-adrenal, retroperitoneal | 1 | c.413T>G | 4 |
| 1/Hungary | 22 | F | Negative | Adrenal, bilateral | 2 | c.419G>A | 5 |
| 1/Germany | 76 | M | Negative | Adrenal, unilateral | 0 | c.462C>G | 4 |
| 1/Hungary | 51 | F | Negative | Adrenal, bilateral, carotid, malignant | 3 | c.464T>A | 5 |
| 1/Germany | 26 | F | Negative | Adrenal, unilateral | 1 | c.518T>C | 4 |
| 1/Poland | 25 | F | Negative | Adrenal, unilateral | 1 | c.532dup | 5 |
| 1/Israel | 33 | F | Positive | Adrenal, bilateral | 3 | c.543_555dup | 5 |
| 1/Turkey | 51 | F | Negative | Adrenal, bilateral, extra-adrenal retroperitoneal | 2 | c.553G>A | 4 |
| 1/Germany | 50 | F | Negative | Tympanic | 1 | c.568G>A | 4 |
| 2/Turkey and Hungary | 26 and 47 | F | Negative | Adrenal, unilateral; adrenal, bilateral | 1 | c.572del | 5 |
| 1/Sweden | 55 | F | Negative | Adrenal, unilateral | 0 | c.665C>T | 3 |
| MAX | |||||||
| 1/Germany | 36 | F | Negative | Adrenal, unilateral | 1 | c.73C>T | 5 |
| 1/Germany | 23 | F | Negative | Adrenal, unilateral | 1 | c.146C>G | 5 |
| 3/Germany and Poland | 32-38 | M and F | Negative and positive | Adrenal, unilateral; adrenal bilateral | 1-3 | c.223C>T | 5 |
| 1/Germany | 50 | F | Positive | Adrenal, bilateral | 2 | c.242_243del | 5 |
| 1/Germany | 21 | M | Negative | Adrenal, unilateral | 1 | c.292dup | 5 |
| 1/Germany | 26 | M | Negative | Adrenal, bilateral | 2 | c.307G>T | 5 |
| SDHAF2 | |||||||
| 1/United States | 25/ | F | Positive | Carotid, vagal | 3 | c.232G>A | 5 |
Abbreviations: ACMG, American College of Medical Genetics and Genomics; MAX, Myc-associated factor X; SDHA, succinate dehydrogenase subunit A; SDHAF2, succinate dehydrogenase complex assembly factor 2; TMEM127, transmembrane protein 127.
Indicates status before clinical surveillance imaging.
Includes a family history of pheochromocytomas and paragangliomas; younger than 40 y at diagnosis; more than 1 pheochromocytoma or paraganglioma; tumor location outside the adrenal glands; and malignant tumor.
Classified according to the variant classification system of the ACMG. Class 3 indicates variant of unknown clinical significance; class 4, likely pathogenic; and class 5, certainly pathogenic. Fifty-eight index patients had certain (class 5) or likely pathogenic (class 4) mutations, and 6 index patients had DNA variants of unknown significance (class 3). The latter 6 (5 SDHA and 1 TMEM127) with DNA variants of unknown clinical significance were not included in additional analyses.