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IKZF5 Gene Curation

IKZF5 Gene Curation

Owned by Kelley Paris
2024-12-18
3 min read

Gene-disease assertions not curated here (add link or write note):

Disease

Thrombocytopenia

Disease

Thrombocytopenia

Inheritance

Autosomal dominant

Prevalence

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

 

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

PMID: 31217188

  • 5 missense variants (Y89C, R96W, G134E, C140R, and H155Y) in or near IKZF5 zinc fingers in patients with isolated thrombocytopenia identified by WES (all absent from gnomAD v4) - 0.1*5 = 0.5 pts

PMID: 32419556

  • Identified c.355T>C (p.Ser119Pro) variant in a proband with with severe bleeding tendency and lifelong thrombocytopenia (absent from gnomAD v4) - 0.1 pt

  • Identified c.48G>C (p.Gln16His) variant in another proband (from a different family) with thrombocytopenia (absent from gnomAD v4) - 0.1 pt

ClinVar:

  • c.296_300delinsTGTGGATT (p.Glu99_His100delinsValTrpIle) seen in patient with Thrombocytopenia 7 (submitted by Baylor Genetics, absent from gnomAD v4) - 0.1 pt

 

Segregation Evidence:

PMID: 31217188

  • H155Y and C140R were de novo - 1 pt for segregation

  • G134E seen in 4 affected family members and 1 unaffected family member (LOD score: 1.505) - 0 pts for segregation

  • R96W segregated in 6 affected family members (LOD score: 1.806) - 0 pts for segregation

  • Y89C segregated in 2 affected family members (LOD score: 0.602) - 0 pts for segregation

 

Case/Control Evidence:

Experimental Evidence:

PMID: 31217188

  • In contrast to WT IKZF5, which enters the nucleus to bind to chromatin, all 5 causal mutants exhibited a strong reduction in chromatin binding, remaining instead in the cytosol and soluble membranes fractions - 0.5 pts (functional data)

  • Quantified proplatelet formation (PPF) after MK spreading on fibrinogen and staining with VWF and found it to be significantly reduced in 7 cases from 3 pedigrees compared with 6 unrelated healthy controls - 0.5 pts (functional data)

  • RNA sequencing revealed that platelet transcriptome of members from 3 pedigrees was different from controls. In particular, genes linked to platelet formation and function were deregulated and this explains thrombocytopenia and reduced platelet alpha-granules - 0.5 pts (functional data)

PMID: 32419556

  • In the proband with the p.Ser119Pro variant, light microscopy demonstrated unusual platelet morphology (platelets were elongated and often presented as proplatelets with 3–5 platelets still aligned connected by a cytoplasmic bridge). Flow cytometry analysis of the proband’s platelets demonstrated reduced size scatter indicating small platelet size - 0.5 pts (functional data)

  • In the proband with the p.Gln16His variant, light microscopy demonstrated platelets of variable size and shape. Platelets were elongated, sometimes resembling pro-platelets - 0.5 pts (functional data)

PMID: 10978333

  • IKZF5 is expressed in peripheral blood leukocytes, MEG-01 and M07e cell lines (megakaryocytic cell lines) - 1 pt

Source:

Clinical Validity Points Total

 

Source:

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Limited (5.3 pts)

Source:

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Dominant Negative

PMIDs: 7585946, 10473095, 31217188

 

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Source:

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

 

Severity

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

- 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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