Gene-disease assertions not curated here (add link or write note):
Katie Russell is a Broad expert on ABCC8 - she shared these slides https://docs.google.com/presentation/d/1Lw5xnS3-EUYBMeSBMQ9euHRG45imqOWDTQ6KRSdGiw8/edit#slide=id.p Her summary -
Image AddedCHI
AR - caused by LOF
Some patients with somatic UPD of the pancreas of carriers can develop focal CHI
AD - dominant negative
Did not curate Semidominant monogenic diabetes (MODY) - definitive (GOF / activating mutations by Monogenic diabetes GCEP. They note that inactivating LOF variants cause hyperinsulinemic hypoglycemia.
Did not curate pulmonary arterial hypertension - not well established per above
Disease | Familial hyperinsulinism, aka congenital hyperinsulinism (CHI), hyperinsulinemic hypoglycemia |
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Inheritance | autosomal recessive |
Prevalence | Source: |
Rapid or full curation? | |
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 |
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| title | Classifications (pts) |
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| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
| Strong |
Molecular Mechanism | Expand |
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| Loss of function Gain of function Dominant negative Unknown Other |
| Loss of function NM_000352.3(ABCC8):c.4014G>A(W1338*) - 24932607_Durmaz_2014 Homozygous in patient with congenital hyperinsulinism, diffuse HI determined via histological findings from near-total pancreatecomy at 2 months of age.
M_000352.3(ABCC8):c.3868-1G>A - 23345197_Kapoor_2013 Homozygous in a patient with Congenital hyperinsulism, diffuse HI determined via histological findings from near-total pancreatecomy.
NM_000352.3(ABCC8):c.3509delT(L1170Rfs*38) - 24686051_Demirbilek_2014 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 |
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| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | Source: |
Age of Onset | Expand |
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| Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | |
Severity | Expand |
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| 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. |
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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 |
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| - 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 |
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Case ID, Curator name, Date, Jira ticket link | |
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