Table 3.
Comparison of Frequencies of Missense Germline AIP Variants Reported in 1866 Individuals With Sporadic Pituitary Tumors and the ExAC Cohort
| Total Missense AIP Variants With AF <0.5% (n) | Arg9Gln (n) | Arg16His (n) | Arg304Gln (n) | Ala299Val (n) | ExAC Othera (n) | Novel Singletonb (n) | |
|---|---|---|---|---|---|---|---|
| All (n = 1866) | |||||||
| Observed in sporadic pituitary tumor cohorts | 38 | 2 | 12 | 9 | 0 | 7 | 8 |
| Predicted from Global ExAC variant frequencies | 26.7 | 0.8 | 7.3 | 5.4 | 1.6 | 9.4 | 2.0 |
| Odds ratio (95% CI) observed vs predicted | 1.4 (1.0–2.0) | — | 1.6 (0.9–2.9) | 1.6 (0.8–3.2) | — | — | 4.1 (1.9–8.5) |
| Observed in sporadic pituitary tumor cohorts | 38 | 2 | 12 | 9 | 0 | 7 | 8 |
| Predicted from European ExAC variant frequencies | 30.2 | 1.1 | 11.2 | 9.1 | 2.5 | 4.7 | 1.6 |
| Odds ratio (95% CI) observed vs predicted | 1.2 (0.9–1.7) | — | 1.1 (0.6–1.9) | 1.0 (0.5–1.9) | — | — | 5.2 (2.3–11.4) |
| Acromegaly (n = 935) | |||||||
| Observed in acromegaly cohort | 18 | 0 | 6 | 5 | 0 | 1 | 6 |
| Predicted from global ExAC variant frequencies | 13.2 | 0.4 | 3.6 | 2.7 | 0.8 | 4.7 | 1 |
| Odds ratio (95% CI) observed vs predicted | 1.3 (0.8–2.1) | — | — | — | — | — | — |
| Observed in acromegaly cohort | 18 | 0 | 6 | 5 | 0 | 1 | 6 |
| Predicted from European ExAC variant frequencies | 15.1 | 0.5 | 5.6 | 4.6 | 1.2 | 2.4 | 0.8 |
| Odds ratio (95% CI) observed vs predicted | 1.2 (0.7–1.9) | — | — | — | — | — | — |
| Prolactinoma (n = 359) | |||||||
| Observed in prolactinoma cohort | 13 | 1 | 1 | 3 | 0 | 6 | 2 |
| Predicted from global ExAC variant frequencies | 5.1 | 0.2 | 1.4 | 1 | 0.3 | 1.8 | 0.4 |
| Odds ratio (95% CI) observed vs predicted | 2.6 (1.5–4.5) | — | — | — | — | — | — |
| Observed in prolactinoma cohort | 13 | 1 | 1 | 3 | 0 | 6 | 2 |
| Predicted from European ExAC variant frequencies | 5.8 | 0.2 | 2.1 | 1.8 | 0.5 | 0.9 | 0.3 |
| Odds ratio (95% CI) observed vs predicted | 2.2 (1.3–3.9) | — | — | — | — | — | — |
Germline missense variants reported in 1866 individuals (representing 3732 alleles) with apparently sporadic pituitary tumors in whom the AIP gene was sequenced. Patient groups represented in the respective studies include those with sporadic child gigantism, sporadic acromegaly presenting in young adulthood and sporadic acromegaly presenting at any age, and individuals with other forms of apparently sporadic pituitary adenomas [including prolactinomas (predominantly macroprolactinomas), nonfunctioning adenomas, and Cushing disease]. This analysis did not include AIP sequence analysis from those individuals with apparent familial isolated pituitary adenoma syndromes or those individuals with MEN1-like disorders. A separate subanalysis comparing allele frequencies between the pituitary tumor cohort and just the European subset of the ExAC cohort (n = 33,370 individuals) was performed, deemed to be the most suitable comparator group for the disease cohorts reported in the literature. Estimates of odds ratios and CIs were calculated at http://www.hutchon.net/confidor.htm. For individual variants, odds ratios are provided only where sufficient numbers of alleles were observed to enable meaningful comparison. Some of the studies included in the analysis, reported individuals with unclassified pituitary tumor subtypes. These individuals are not included in the subgroup analysis of prolactinoma and acromegalic cases.
Abbreviation: CI, confidence interval.
ExAC other: Observed at least once in the ExAC cohort but with an AF <0.5% and excluding R9Q, R16H, R304Q, and A229V variants. AIP variants occurring as singletons in ExAC are also reported in this group.
Novel Singleton: not observed in the ExAC cohort. Predicted number deduced from prevalence of singletons in the ExAC cohort.