The ataxia-telangiectasia gene predisposes heterozygotes to cancer, particularly breast cancer in women. There is also excess mortality from all causes in adults under the age of 60. Diagnostic or occupational exposure to ionizing radiation probably increases the risk of breast cancer in women heterozygous for ataxia-telangiectasia.

Patients who are homozygous for ataxia-telangiectasia have an exceptionally high incidence of cancer. In a group of families expected to have a high proportion of heterozygotes for ataxia-telangiectasia, we tested the hypothesis that such heterozygotes, estimated to make up 0.68 to 7.7 percent of the U.S. white population, also have an excess cancer risk. Retrospective cancer incidence rates in adult blood relatives of patients with ataxia-telangiectasia in 110 white non-Amish families were significantly elevated over the incidence rates in spouse controls (rate ratios, 1.6 for men [P = 0.032]; 2.0 for women [P = 0.013]). For persons who are heterozygous for ataxia-telangiectasia, the relative risk of cancer was estimated to be 2.3 for men (P = 0.014) and 3.1 for women (P = 0.004). Breast cancer in women was the cancer most clearly associated with heterozygosity for ataxia-telangiectasia (rate ratio, 3.0 [P = 0.028]; heterozygote relative risk, 6.8 [P = 0.006]). On the basis of this estimated relative risk of 6.8 and an estimated heterozygote frequency in the general population of 1.4 percent, 8.8 percent of patients with breast cancer in the U.S. white population would be heterozygous for ataxia-telangiectasia. We conclude that heterozygous carriers of the gene for ataxia-telangiectasia have an excess risk of cancer, particularly breast cancer in women.

Obesity and renal failure are common manifestations in the autosomal recessive Bardet-Biedl (BB) syndrome. Because obesity and hypertension have been reported frequently in non-homozygous relatives of BB patients, we hypothesized that BB heterozygotes are predisposed to these conditions. Clinical information was collected from 34 patients of BB homozygotes, who are obligate heterozygotes. The proportion of severely overweight fathers (26.7%) was significantly higher than that in comparably aged United States white males (8.9%). We conclude that the BB gene may predispose male heterozygous carriers to obesity. If BB heterozygotes are 1% of the general population, we estimate that approximately 2.9% of all severely overweight white males carry a single BB gene. The BB parents of both sexes were also significantly taller than U.S. white men and women of comparable age.

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The hypothesis that heterozygous carriers of genes for certain autosomal recessive syndromes may be predisposed to diabetes was tested by comparing diabetes incidence from age 20 to 69 yr in blood relatives to that in spouse controls among 7999 adult family members of patients with one of five autosomal recessive syndromes: ataxia-telangiectasia (A-T), Fanconi anemia (FA), xeroderma pigmentosum (XP), common variable immune deficiency (CVID), and severe combined immune deficiency (SCID). FA and A-T families were studied because earlier findings in family members and the frequency of diabetes in homozygotes suggested that heterozygotes might also be predisposed to diabetes. The XP, CVID, and SCID families were included to see what analysis of family data would reveal when there was no prior evidence for a gene-diabetes association. The diabetes rate ratios of 2.6 and 4.2 among FA and SCID females, respectively, were significantly elevated. For female FA heterozygotes specifically, the estimated relative risk of 5.1 for developing diabetes was also significantly elevated. Among males, the most pronounced, although not statistically significant, findings were an elevated rate ratio of 2.2 for A-T males and a low-rate ratio of 0.5 for CVID males. The results suggest that heterozygotes for some of the diabetes-associated autosomal recessive syndromes may themselves be predisposed to diabetes.