Neonatal diabetes

Gene: EIF2B1

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.

Created: 31 Jan 2023, 4:43 p.m. | Last Modified: 31 Jan 2023, 4:43 p.m.

Panel Version: 3.3

Comment on list classification: Promoting to amber, but with a recommendation for green status.

Created: 27 Sep 2022, 1:49 p.m. | Last Modified: 27 Sep 2022, 1:49 p.m.

Panel Version: 2.49

Associated with Leukoencephalopathy with vanishing white matter, #603896 (AR) in OMIM.

As expert reviewer reports De Franco et al 2020 (PMID:31882561) screened patients with Permanent neonatal diabetes (PNDM) and early onset diabetes using a targeted next generation sequencing assay, including the known monogenic diabetes genes and additional candidate genes, such as EIF2B1. 5 de novo EIF2B1 variants were identified, p.(Gly44Asp), p.(Gly44Val), p.(Ser77Asn), p.(Leu34Trp), p.(*306Thrext*12). Onset of diabetes was at 21 weeks or less in 4 patients, and at 56 weeks in the 5th. The patients do not exhibit severe neurological features seen in cases with homozygous variants in EIF2B1 but two reported cases displayed mild learning disability or attention deficit disorder.

Created: 27 Sep 2022, 1:48 p.m. | Last Modified: 27 Sep 2022, 11:40 p.m.

Panel Version: 2.57

Review on behalf of Jayne Houghton and Kevin Colclough, Exeter Genomics Laboratory, SWGLH. Trio whole genome sequencing in patients with permanent neonatal diabetes and their parents for whom all the known genetic causes for neonatal diabetes had been excluded identified de novo variants in the EIF2B1 gene. To date there are 5 reported cases (De Franco et al 2020 Diabetes; PMID: 31882561). The patients presented with diabetes between the ages of 4 and 56 weeks and were treated with full insulin replacement doses. The 4 patients for whom data was available had low birth weight (<20th centile, SDS range -0.84- -1.74) consistent with reduced insulin secretion in utero. The variants, 4 missense and one stop-loss, are all predicted to map to the same protein surface and in silico modelling suggests that they are likely to disrupt the interaction of the EIF2Ba subunit (encoded by EIF2B1) with phosphorylated EIF2a during the cell Integrated Stress Response. These patients clinical features are markedly different from those reported in patients with leukoencephalopathy with vanishing white matter (VWM), a rare paediatric neurological disease caused by recessive loss-of-function EIF2B1 mutations. VWM is a progressive condition usually fatal in childhood. Extra-neurological features are generally not present. None of the 5 patients reported by De Franco et al had severe neurological features. The heterozygous carrier parents of VWM patients are clinically unaffected supporting the hypothesis that the variants identified in patients presenting with neonatal diabetes do not result in complete loss of function of the eIF2B complex.

Created: 14 Sep 2022, 4:42 p.m. | Last Modified: 14 Sep 2022, 4:42 p.m.

Panel Version: 2.40

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Permanent neonatal/early onset diabetes and transient liver dysfunction.

Publications

• 31882561