Congenital hyperinsulinism

Gene: CACNA1D

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 31 Jan 2023, 4:38 p.m. | Last Modified: 31 Jan 2023, 4:38 p.m.

Panel Version: 2.32

Green List (high evidence)

Associated with phenotype in OMIM and as strong Gen2Phen gene for Primary aldosteronism, seizures, and neurologic abnormalities (OMIM:615474). Two variants have been reported in two unrelated cases of congenital hyperinsulinaemic hypoglycaemia; PMID: 28318089 reports: c.1319G>A (p.G403D) in a case who also has heart defects and severe hypotonia and PMID: 32336187 reports: c.812T>A (p.L271H) in a case who also has primary hyperaldosteronism and hypotonia. A third de novo case has been reported in the review provided by Eleanor Williams on behalf of Jayne Houghton and Kevin Colclough, Exeter Genomics Laboratory, SWGLH.

Created: 27 Sep 2022, 1:36 p.m. | Last Modified: 27 Sep 2022, 1:36 p.m.

Panel Version: 2.23

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 27 Sep 2022, 1:12 p.m. | Last Modified: 27 Sep 2022, 1:12 p.m.

Panel Version: 2.23

Review on behalf of Jayne Houghton and Kevin Colclough, Exeter Genomics Laboratory, SWGLH. Variants causing congenital hyperinsulinism have been identified in 3 patients to date. The first reported case (Flanagan et al 2017 PMID : 28318089) identified a de novo variant in a patient with congenital hyperinsulinism, heart defect and severe hypotonia. A second de novo case with congenital hyperinsulinism, primary hyperaldosteronism and hypotonia was was reported by De Mingo Alemany et al 2020 PMID:32336187, and a third de novo case has been identified by the Exeter genomics laboratory in a patient diagnosed with congenital hyperinsulinism, hypertrophic cardiomyopathy and hypotonia.

Created: 14 Sep 2022, 4:39 p.m. | Last Modified: 14 Sep 2022, 4:39 p.m.

Panel Version: 2.12

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

Phenotypes
congenital hyperinsulinism, hypotonia and heart defects

Publications

• 28318089
• 32336187

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
hyperinsulinaemic hypoglycaemia, heart defects; severe hypotonia

Publications

• 28318089

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

There is currently insufficient evidence for the promotion of this gene to a different gene status; therefore, it will remain red for now.

Created: 31 Jul 2019, 1:48 p.m. | Last Modified: 31 Jul 2019, 1:48 p.m.

Panel Version: 1.52

Initial gene list and info collated by Sian Ellard, University of Exeter Medical School, August 2018 on behalf of the GMS Endocrinology specialist test group. Gene Symbol submitted: CACNA1D; Suggested intial gene rating: Green; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given; Phenotypes: Autosomal dominant hyperinsulinism with heart defects and severe hypotonia.

Created: 11 Jan 2019, 2:24 p.m.