Versions Compared

Version Old Version 1 New Version Current
Changes made by

Andrea Oza

Andrea Oza

Saved on

Key

  • This line was added.
  • This line was removed.
  • Formatting was changed.

...

Disease

Congenital isolated adrenocorticotropic hormone deficiency

Inheritance

Autosomal recessive

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 unknown

Source:

Rapid or full curation?

  •  Rapid - molecular mechanism only needed
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none. GenCC - Definitive (Ambry), Strong (Invitae). No scoring needed.

Clinical Validity Scoring Notes and points

n/a

Source:

Clinical Validity Points Total

n/a

Source:

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function

  1. c.82C>T p.Q28* - NMD+, but variant at high-ish frequency in gnomAD in 0.1% (104/64032) European chr. in family I, segregates in affected sib, both unaffected parents and unaffected sibs are het only. Patients from this cohort had neonatal-onset ACTH deficiency in the absence of other pituitary hormone deficiency and any identified cause of hypocortisolism (PMID: 15613420)

  2. c.856C>T p.R286* - NMD +, low enough frequency in gnomAD for AR disease 0.001% (21/1180034) European chr. Present in family IV. Patients from this cohort had neonatal-onset ACTH deficiency in the absence of other pituitary hormone deficiency and any identified cause of hypocortisolism (PMID: 15613420)

  3. c.535C>T p.R179* - Grpmax 0.00004700 (69/1179872) in gnomAD. Variant homozygous in patient 1 from family 1. PMID: 12651888

  4. Homozygous null mouse model had very low, but detectable plasma ACTH (PMID: 12651888)

PMID: 15613420, 12651888

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

The TBX19 gene is associated with autosomal recessive congenital isolated adrenocorticotropic hormone deficiency. It is characterized by very low plasma ACTH levels and very low plasma cortisol levels. It presents with severe hypoglycemia in the neonatal period that can result in seizures. Affected individuals may also have cholestasis and/or jaundice (PMID: 15613420, 12651888).

Case ID, Curator name, Date, Jira ticket link

AO 01.13.2025 2106076990 SM-MPQ1F D-101206607-BH-4159-P-A