Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus.

Francis H Sansbury,Sarah E Flanagan,Sian Ellard,Andrew T Hattersley,Richard Caswell,Birgül Kirel,Charles J Shaw-Smith,Hana Lango Allen

doi:10.1038/ejhg.2015.161

Abstract

Neonatal diabetes is a highly genetically heterogeneous disorder. There are over 20 distinct syndromic and non-syndromic forms, including dominant, recessive and X-linked subtypes. Biallelic truncating or mis-sense mutations in the DNA-binding domain of the RFX6 transcription factor cause an autosomal recessive, syndromic form of neonatal diabetes previously described as Mitchell–Riley syndrome. In all, eight cases have been reported, with the age at onset of diabetes in the first 2 weeks of life. Here we report two individuals born to double first cousins in whom intestinal atresias consistent with a diagnosis of Mitchell–Riley syndrome were diagnosed at birth, but in whom diabetes did not present until the ages of 3 and 6 years. Novel compound heterozygous RFX6 nonsense mutations (p.Arg726X/p.Arg866X) were identified at the 3′ end of the gene. The later onset of diabetes in these patients may be due to incomplete inactivation of RFX6. Genetic testing for RFX6 mutations should be considered in patients presenting with intestinal atresias in the absence of neonatal diabetes.

Highlights

Neonatal diabetes is defined as diabetes diagnosed within the first 6 months of life
Genetic testing Genomic DNA was extracted by standard protocols and the proband was tested for mutations in all known neonatal diabetes genes using a previously described targeted generation sequencing assay.[11]
We report double first cousins in whom the identification of biallelic RFX6 mutations has confirmed a diagnosis of Mitchell–Riley syndrome

Summary

Introduction

Neonatal diabetes is defined as diabetes diagnosed within the first 6 months of life It is highly genetically heterogeneous, with dominant, recessive and X-linked patterns of inheritance well described, comprising to date over 20 distinct syndromic and non-syndromic forms with a combined incidence of around 1 in 100 000 births.[1]. Biallelic mutations in RFX6 (regulatory factor X, 6) cause neonatal diabetes mellitus in association with intestinal atresias, and hepatobiliary abnormalities This condition has been designated as Mitchell–Riley syndrome.[5] To date there have been eight genetically confirmed cases, comprising seven probands and one sibling.[5,6,7,8,9,10] Typically, fetal abnormality is suspected pre-natally and a diagnosis of duodenal and/or jejunal atresia confirmed shortly after birth. With death occurring within the first 6 months in five of the cases described to date

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Results

Conclusion