ESPE Abstracts (2019) 92 P1-32

Heterozygous RFX6 Mutation as a Cause of Diabetes Mellitus in a Multigenerational Family

Nehama Zuckerman Levin1,2, Tamar Paperna3, Tova Hershkovitz 3,2, Adi Mory3, Alina Kurolap 3,2, Jamal Mahameed4, Hagit Baris Feldman3,2, Naim Shehadeh1,2


1Pediatric Diabetes Clinic, Institute of Diabetes, Endocrinology and Metabolism, Rambam Health Care Campus, Haifa, Israel. 2The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. 3The Genetics institute, Rambam Health Care Campus, Haifa, Israel. 4Meuhedet Health services, Umm El Fahem, Israel


Background: Monogenic diabetes mellitus (DM) is an early-onset, non- autoimmune diabetes. Genetic diagnosis can personalize patient management and lead to prevention. We describe four generations of DM in one family, caused by a heterozygous mutation in the RFX6 gene. RFX6 (Regulatory factor X, 6) is essential for the development of the endocrine pancreas. Mutations in RFX6 can cause neonatal (Mitchell-Riley syndrome) as well as childhood DM, intestinal atresia and hepatobiliary abnormalities.

Patients and Methods: Transient, stress hyperglycemia was the first clinical presentation of our patient at the age of 3 years. Non-autoimmune DM was diagnosed at 13 years. Maternal family history revealed great-grandmother, grandmother and a mother, two aunts and one cousin with DM. They were diagnosed as diabetics in adolescence or young adulthood. Only the patient's mother was treated by insulin.

Next generation panel sequencing for genes of monogenic DM, using the Trusight One platform (Illumina), was utilized for genetic analysis of the proband. Sanger sequencing was performed to validate the likely- pathogenic finding and for segregation analysis in the family.

Results: We identified a heterozygous mutation in RFX6 gene (c.781-2_787delinsG affecting intron7/exon 8) in the proband that co-segregated in five family members with DM, and in the patient's healthy brother and two young cousins. One uncle who carries the mutation has asymptomatic DM. This mutation was previously reported to cause autosomal recessive neonatal diabetes.

Conclusions: Heterozygous RFX6 mutation was diagnosed as the cause of familial DM. Genetic evaluation of youth with non – autoimmune DM provides accurate diagnosis and identifies subjects at risk.

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