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. 2017 Aug;66(8):2316-2322.
doi: 10.2337/db17-0040. Epub 2017 May 4.

Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes

Matthew B Johnson  1 , Elisa De Franco  1 , Hana Lango Allen  1 , Aisha Al Senani  2 , Nancy Elbarbary  3 , Zeynep Siklar  4 , Merih Berberoglu  4 , Zineb Imane  5 , Alireza Haghighi  6   7   8 , Zahra Razavi  9 , Irfan Ullah  10 , Saif Alyaarubi  10 , Daphne Gardner  11 , Sian Ellard  1 , Andrew T Hattersley  12 , Sarah E Flanagan  1
Affiliations

Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes

Matthew B Johnson et al. Diabetes. 2017 Aug.

Erratum in

Abstract

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.

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Conflict of interest statement

Conflict of interest statement

No potential conflicts of interest relevant to this article were reported.

Figures

Figure 1
Figure 1. Family pedigrees of patients with LRBA mutations.
Filled symbols represent affected individuals and dots within symbols represent heterozygous unaffected carriers. Double lines signify parents are related. Genotypes are provided below affected individuals and carriers. When no genotype is given, samples were unavailable for testing.
Figure 2
Figure 2. Flow diagram showing the testing strategy for LRBA screening in individuals diagnosed with diabetes diagnosed before 12 months of age.
The pick up rates of LRBA mutations, when individuals are subgrouped according to consanguinity and additional autoimmune disease, are provided.
See this image and copyright information in PMC

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