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Andrea Oza

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Disease

Familial hyperinsulinism, aka congenital hyperinsulinism (CHI), hyperinsulinemic hypoglycemia

Inheritance

autosomal recessive

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 

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

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Strong

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

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 -

Penetrance

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

Expand
titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

Expand
titleOptions

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

Clinical Features

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

Expand
titleExamples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

Case ID, Curator name, Date, Jira ticket link

Disease

Familial hyperinsulinism, aka congenital hyperinsulinism (CHI), hyperinsulinemic hypoglycemia

Inheritance

autosomal dominant

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clinical Validity Scoring Notes and points

Clinical Validity Points Total

Source:

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Strong

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

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.

Penetrance

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

Expand
titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

Expand
titleOptions

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

Clinical Features

Phenotype is clinically indistinguisable from 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

Expand
titleExamples

  • The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

  • Variable expression or severity:


The severity and expressivity of the disorder is highly variable, even within families.

  • If multiple conditions associated with the gene:


It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

  • Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

Case ID, Curator name, Date, Jira ticket link