Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes

Matthew B. Johnson, Elisa De Franco, Hana Lango Allen, Aisha Al Senani, Nancy Elbarbary, Zeynep Siklar, Merih Berberoglu, Zineb Imane, Alireza Haghighi, Zahra Razavi, Irfan Ullah, Saif Alyaarubi, Daphne Gardner, Sian Ellard, Andrew T. Hattersley*, Sarah E. Flanagan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Citations (SciVal)


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.

Original languageEnglish
Pages (from-to)2316-2322
Number of pages7
Issue number8
Publication statusPublished - Aug 2017

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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