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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2316-2322
Number of pages7
JournalDiabetes
Volume66
Issue number8
DOIs
Publication statusPublished - Aug 1 2017

Fingerprint

Autoimmunity
Mutation
Parents
Autoimmune Lymphoproliferative Syndrome
Common Variable Immunodeficiency
Exome
Genetic Counseling
Type 1 Diabetes Mellitus
Genes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Johnson, M. B., De Franco, E., Allen, H. L., Al Senani, A., Elbarbary, N., Siklar, Z., ... Flanagan, S. E. (2017). Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes. Diabetes, 66(8), 2316-2322. https://doi.org/10.2337/db17-0040

Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes. / Johnson, Matthew B.; De Franco, Elisa; Allen, Hana Lango; Al Senani, Aisha; Elbarbary, Nancy; Siklar, Zeynep; Berberoglu, Merih; Imane, Zineb; Haghighi, Alireza; Razavi, Zahra; Ullah, Irfan; Alyaarubi, Saif; Gardner, Daphne; Ellard, Sian; Hattersley, Andrew T.; Flanagan, Sarah E.

In: Diabetes, Vol. 66, No. 8, 01.08.2017, p. 2316-2322.

Research output: Contribution to journalArticle

Johnson, MB, De Franco, E, Allen, HL, Al Senani, A, Elbarbary, N, Siklar, Z, Berberoglu, M, Imane, Z, Haghighi, A, Razavi, Z, Ullah, I, Alyaarubi, S, Gardner, D, Ellard, S, Hattersley, AT & Flanagan, SE 2017, 'Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes', Diabetes, vol. 66, no. 8, pp. 2316-2322. https://doi.org/10.2337/db17-0040
Johnson MB, De Franco E, Allen HL, Al Senani A, Elbarbary N, Siklar Z et al. Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes. Diabetes. 2017 Aug 1;66(8):2316-2322. https://doi.org/10.2337/db17-0040
Johnson, Matthew B. ; De Franco, Elisa ; Allen, Hana Lango ; Al Senani, Aisha ; Elbarbary, Nancy ; Siklar, Zeynep ; Berberoglu, Merih ; Imane, Zineb ; Haghighi, Alireza ; Razavi, Zahra ; Ullah, Irfan ; Alyaarubi, Saif ; Gardner, Daphne ; Ellard, Sian ; Hattersley, Andrew T. ; Flanagan, Sarah E. / Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes. In: Diabetes. 2017 ; Vol. 66, No. 8. pp. 2316-2322.
@article{efb54f835be44ff49a7dc1aa5dc7dfb9,
title = "Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes",
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.",
author = "Johnson, {Matthew B.} and {De Franco}, Elisa and Allen, {Hana Lango} and {Al Senani}, Aisha and Nancy Elbarbary and Zeynep Siklar and Merih Berberoglu and Zineb Imane and Alireza Haghighi and Zahra Razavi and Irfan Ullah and Saif Alyaarubi and Daphne Gardner and Sian Ellard and Hattersley, {Andrew T.} and Flanagan, {Sarah E.}",
year = "2017",
month = "8",
day = "1",
doi = "10.2337/db17-0040",
language = "English",
volume = "66",
pages = "2316--2322",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "8",

}

TY - JOUR

T1 - Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes

AU - Johnson, Matthew B.

AU - De Franco, Elisa

AU - Allen, Hana Lango

AU - Al Senani, Aisha

AU - Elbarbary, Nancy

AU - Siklar, Zeynep

AU - Berberoglu, Merih

AU - Imane, Zineb

AU - Haghighi, Alireza

AU - Razavi, Zahra

AU - Ullah, Irfan

AU - Alyaarubi, Saif

AU - Gardner, Daphne

AU - Ellard, Sian

AU - Hattersley, Andrew T.

AU - Flanagan, Sarah E.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85025589790&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85025589790&partnerID=8YFLogxK

U2 - 10.2337/db17-0040

DO - 10.2337/db17-0040

M3 - Article

C2 - 28473463

AN - SCOPUS:85025589790

VL - 66

SP - 2316

EP - 2322

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 8

ER -