Inheritance

autosomal recessive

Prevalence

Source:

Rapid or full curation?

•  Rapid
•  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Not in ClinGen. GenCC - Definitive Ambry (Semidominant); Strong (Invitae; AR and AD) - no conflicts - sufficent to say there is enough evidence for a strong GDA.

Clinical Validity Scoring Notes and points

n/a - GenCC provides sufficent evidence that there is a strong association

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

Strong

Molecular Mechanism

Loss of function

1. NM_000352.3(ABCC8):c.4014G>A(W1338*) - 24932607_Durmaz_2014

   1. Homozygous in patient with congenital hyperinsulinism, diffuse HI determined via histological findings from near-total pancreatecomy at 2 months of age.

2. M_000352.3(ABCC8):c.3868-1G>A - 23345197_Kapoor_2013

   1. Homozygous in a patient with Congenital hyperinsulism, diffuse HI determined via histological findings from near-total pancreatecomy.

3. NM_000352.3(ABCC8):c.3509delT(L1170Rfs*38) - 24686051_Demirbilek_2014

   1. Homozygous in patient w/ congenital hyperinsulism HI that responded to octreotide, developmental delay, and ectodermal dysplasia.

KO mouse model 10734066_Seghers_2000

• SUR1 knockout mice were generated by inserting a puromycin resistance gene into ABCC8 exon 2. Patch clamp assays were used to show that SUR1-/- mice exhibit no K+ current (Fig 2A) and show spontaneous Ca2+ action potentials (Fig 2B), which recapitulates function data from KATP in patient cells. SUR1-/- mice exhibit mild glucose intolerance in response to glucose challenge (Fig 5) and transient neonatal hypoglycemia (Fig 6), however, the mice do not recapitulate the full human hypoglycemic phenotype.

Focal CHI -

• Caused by paternally inherited LOF variant and loss of the maternal allele (usually due to UPD in the pancreas)

Penetrance

(list source/PMID)

Source:Incomplete

Age of Onset

(list source/PMID)

Severity

Clinical Features

inappropriate secretion of insulindespite low blood glucose, which can result in irreversible braindamage if not promptly treated (Helleskov et al., 2017). Thecondition has a variable phenotype usually presenting during the neonatal period or infancy with seizures and/or coma and alarge birth weight due to high levels of insulin acting as a growth factor in utero. (Defranco_2020_32027066)

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

The ABCC8 gene is associated with two different diseases with multiple inheritance patterns. Monogenic diabetes, which also includes known as transient or permanent neonatal diabetes of infancy, is primarily an autosomal dominant disorder caused by activating mutations. Autosomal recessive cases with a partially activating mutation and an inactivating mutation have also been reported. It is characterized by the onset of hyperglycemia within the first six months of life with partial or complete insulin deficiency. Clinical manifestations at the time of diagnosis include intrauterine growth restriction, hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive (PMID: 20301620, 17668386).

Familial hyperinsulinism, also known as congenital hyperinsulinism or hyperinsulinemic hypoglycemia, is primarily an autosomal recessive disorder caused by inactivating (loss-of-function; LOF) variants; however, autosomal dominant cases have also been described and is caused by dominant-negative variants (PMID: 32027066, 20301549, 24814349, 26092864). Furthermore, focal hyperinsulinism is also described in individuals with a paternally inherited inactivating (LOF) mutation and loss of the maternal allele in the pancreatic tissue. Familial hyperinsulinism is characterized by hypoglycemia due to an inappropriate secretion of insulin despite low blood glucose. It can range from mild to severe and present from the newborn period to childhood. In the neonatal period or infancy, it can present with seizures and/or coma, as well as large birth weight (PMID: 20301549, 32027066).

Case ID, Curator name, Date, Jira ticket link

AO 07.26.24, 47230812301136

Inheritance

autosomal dominant

Prevalence

Source:

Rapid or full curation?

•  Rapid
•  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Not in ClinGen.

GenCC:

• Definitive for Semidominant hyperinsulinemic hypoglycemia, familial, 1 by Ambry

• Definitive for AD hyperinsulinemic hypoglycemia, familial, 1 by Illumina

• Strong for AD hyperinsulinemic hypoglycemia, familial, 1 by Invitae

Clinical Validity Scoring Notes and points

n/a - not needed, no conflicts in GenCC

Clinical Validity Points Total Source:

n/a - not needed, no conflicts in GenCC

Clinical Validity Classification

StrongDefinitive based on GenCC submissions

Molecular Mechanism

Dominant-negative

Saint-Martin 2015 PMID: 24814349

• De novo variants include Leu511M, L891P is de novo, L1390P, Asn1481Ile, Asp1506Glu, Ile1512Ser.

• Nine missense (L511M, E825K, K890T, L891P, G1379S, A1459V, N1481I, D1506E, I1512S) ABCC8 mutations were subjected to in vitro expression studies testing traffic efficiency and responses of mutant channels to activation by MgADP and diazoxide. Eight of the 9 missense mutations exhibited normal trafficking (all except G1379S). Seven of the 8 mutants reaching the plasma membrane had dramatically reduced response to MgADP or to diazoxide(<10% of wild-type response) - all except K890T. Expression levels normal, but reduced response - supports dominant negative effect.

Nessa 2015 PMID: 26092864

• 7 different dominant variants described, unresponsive to diazoxide treatment

• 3 variants (D1506E, M1514K, A113V) were co-expressed with WT to investigate a dominant negative effect. 2 experiments performed - 6Rb+ flux and whole-cell patch-clamp. In both of these assays, all the mutants tested impaired the DZX-activated currents but the degree of the effect varied between mutants. However, in all cases it reduced flux and current by over 50% (Fig. 6).

Huopio 2000 11018078

• E1506K found het in 7 patients with CHI and their mothers.All patients had a mild form of CHI that could be managed long-term diazoxide treatment. Mothers did seem to be affected.

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Phenotype is clinically indistinguisable from Same as AR CHI (

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

See above under AR CHI

Case ID, Curator name, Date, Jira ticket link

AO 07.26.24