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Katherine Lafferty

Katherine Lafferty

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Disease

Telomere-related pulmonary fibrosis and/or bone marrow failure syndrome

Inheritance

Autosomal dominant

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

GenCC- AD Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7 (Invitae- Limited 7/13/2023)

OMIM- AD Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

PMID 36028256- 5 variants reported in individuals with idiopathic pulmonary fibrosis (IPF) or familial pulmonary fibrosis (FPF): c.1132dupA p.Thr378fs (0.5pt), c.1123C>T p.Arg375* (0.5pt), c.701G>C p.Arg234Pro (0.1 pt), c.634+1G>T (1pt), c.423_425de lGTC p.Ser142del (0.1 pt). Paper also assessed telomere length but “Individuals carrying [NAF1 variants] did not have significantly shorter WGS-TL although these analyses were limited by small numbers”. (2.2 points)

PMID: 27510903- Two pLOF variants reported in individuals with pulmonary fibrosis/short telomere disease. Individuals with these variants had shorter telomere lengths when compared to family members with out the variants (scored as more specific phenotype with telomere length information): c.984insA p.S329Ifs*12 (2 pt), c.956_957delAA p.K319Rfs*21 (2pt). Segregated in one family in 4 affected individuals (4 points)

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

PMID: 27510903- Cells with truncating mutations showed poor nuclear localization. This function could be rescued by adding an exogenous nuclear localization signal (NLS) (1pt); Mouse model showed NAF1 haploinsufficient mice showed about half the levels of telomeraseRNA component (TR). (2 pts). (3 points)

Source:

Clinical Validity Points Total

At least 9.2- Stopped once at Moderate

Source:

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Moderate

Source:

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

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

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