Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes
De Franco, E
Lango Allen, H
Al Senani, A
American Diabetes Association
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Young-onset autoimmune diabetes associated with additional autoimmunity usually reflects a polygenic predisposition, but rare cases result from monogenic autoimmunity. Diagnosing monogenic autoimmunity is crucial for patients' prognosis and clinical management. We sought to identify novel genetic causes of autoimmunity presenting with neonatal diabetes (NDM) (diagnosis <6 months). We performed exome sequencing in a patient with NDM and autoimmune lymphoproliferative syndrome and his unrelated, unaffected parents and identified compound heterozygous null mutations in LRBA Biallelic LRBA mutations cause common variable immunodeficiency-8; however, NDM has not been confirmed in this disorder. We sequenced LRBA in 169 additional patients with diabetes diagnosed <1 year without mutations in the 24 known NDM genes. We identified recessive null mutations in 8 additional probands, of which, 3 had NDM (<6 months). Diabetes was the presenting feature in 6 of 9 probands. Six of 17 (35%) patients born to consanguineous parents and with additional early-onset autoimmunity had recessive LRBA mutations. LRBA testing should be considered in patients with diabetes diagnosed <12 months, particularly if they have additional autoimmunity or are born to consanguineous parents. A genetic diagnosis is important as it can enable personalized therapy with abatacept, a CTLA-4 mimetic, and inform genetic counseling.
This work was supported by a Wellcome Trust Senior Investigator Award to S.E. and A.T.H. (grant 098395/Z/12/Z). A.T.H. is a National Institute for Health Research Senior Investigator. E.D.F. is a Naomi Berrie Fellow in Diabetes Research. S.E.F. has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 105636/Z/14/Z). Additional support came from the University of Exeter and the National Institute for Health Research Exeter Clinical Research Facility.
This is the author accepted manuscript. The final version is available from American Diabetes Association via the DOI in this record.
Vol. 66 (8), pp. 2316 - 2322
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