between family members. This is analogous to
that in autoimmune lymphoproliferative syndrome, a human genetic immune disorder with
only 60% penetrance among family members
harboring the same heterozygous gene mutation
(27). Contrary to genetic deficiencies in inbred
strains of mice, phenotypic variability is commonly observed in human single-gene disorders
(28). This may explain why D.I.1 has a CTLA4
mutation, yet is asymptomatic. C.I.1 and D.II.2
are apparently healthy because of incomplete
penetrance; however, further immunological testing is required to confirm this assumption. We
did not identify any common genetic modifiers
in this study, as proven by our cohort analysis
(see supplementary text). Also, our analysis of
nonsynonymous SNVs in the CTLA4 coding
region showed that CTLA-4 expression and T
cell function are comparable to those of wild-type controls (table S3 and figs. S9 and S10).
Nonetheless, our findings show that the mutations reported here result in quantitative reductions in CTLA-4 expression, which contribute to
a severe loss of tolerance and infiltrative autoimmune disease.
Our results show the spectrum of clinical
complications that can be anticipated from
CTLA-4–blocking drugs. Consistent with these
findings, treatment with the CTLA-4 mimetic,
CTLA-4–Ig, suppressed patient T cell hyper-
proliferation in vitro (Fig. 3D) and could be a
potential therapeutic intervention for CTLA-4–
deficient patients. Taken together, our results show
that heterozygous CTLA4 mutations in humans
are associated with a severe immunoregula-
tory disorder, which we term CTLA-4 haploinsuf-
ficiency with autoimmune infiltration (CHAI)
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We thank the referring physicians, as well as the patients and
families. The data are tabulated in the main paper and in the
supplementary materials. Supported by the Intramural Research
Program, NIH Clinical Center (H.S.K., T.A.F., J.S., J.E.N., L.R.F.);
the Division of Intramural Research, National Institute of Allergy
and Infectious Diseases (B.L., Y.Z., V.K.R., H.C.S., Y.R., K.N.O.,
S.Pr., S.M.H., M.J.L., G.U.); the National Cancer Institute under
contract HHSN261200800001E (C.A.F.); National Institute of
Allergy and Infectious Diseases grant 5R01HL113304-01 (D.Q. T.);
the National Health and Medical Research Council of Australia
(E.K.D., S.G. T.); Cancer Council NSW (S.G. T.); and National
Institute of Allergy and Infectious Diseases grants AI071087,
AI095848, and AI061093 (E.M.). The content of this publication
does not necessarily reflect the views or policies of the U.S.
Department of Health and Human Services, nor does mention of
trade names, commercial products, or organizations imply
endorsement by the U.S. Government. The sequencing data are
deposited in dbGaP under accession no. phs000797.v1.p1.
Materials and Methods
Figs. S1 to S10
Tables S1 to S3
12 May 2014; accepted 2 September 2014
Published online 11 September 2014;