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ZFPM2 Gene Curation

ZFPM2 Gene Curation

Owned by Katherine Lafferty
Last updated: 2024-11-27
4 min read

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

Disease

ZFPM2-associated congenital heart defects

Disease

ZFPM2-associated congenital heart defects

Inheritance

Autosomal dominant

Prevalence

Orphanet

Medline Plus Genetics

 1:100 births (non-specific)

Source: American Heart Association https://www.heart.org/en/health-topics/congenital-heart-defects/about-congenital-heart-defects

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen- In Scope CHD GCEP

 

GenCC-

Tetralogy of Fallot: Strong (Ambry), Limited (Invitae and G2P)

46,XY sex reversal 9: Strong (Invitae)

Diaphragmatic hernia 3: Strong (Invitae), Limited (G2P)

 

OMIM- Tetralogy of Fallot, 46,XY sex reversal 9, Diaphragmatic hernia 3

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

PMID 14517948- Two missense variants reported in individuals with TOF, E30G (c.88A>G) and S657G (c.1968A>G). S657G showed subtly reduced function in GATA4 activation. Did not feel this functional evidence was enough to upgrade score (no score, all high freq in gnomAD)

PMID: 20807224- Three missense variants identified in individuals with DORV and TOF: 89A>G Glu30Gly, 679A>G Ile227Val, 1632G>A Met544Ile. Each were absent from 1000 control chromosomes. (no score, all high freq in gnomAD)

PMID: 27058611- One proband with atrioventricular septal defect compound het (confirmed in trans) for p.E30G & p.S388G. p.E30G high freq variant. (0.1 pt for p.S388G b/c absent from gnomAD)

PMID: 25025186- Four missense variants in six individuals with DORV and TOF (p.V339I in DORV C121, p.A426T in DORV C21, p.M703L in TOF C067, C079,C183, p.T843M in TOF C076). Variants were absent from 100 healthy ethnicity-matched controls. All present in gnomAD at fairly high freq. The lowest freq is p.T843M which was is seen in at an AF of 0.026% in South Asian population (this paper is a Chinese cohort). The study took variants many reported variants in both this study and the literature and looked at interaction with GATA4 through GST pull-down assays. p.M544I and p.K737E subtly impaired the binding.

PMID: 24769157- Nonsense variant p.Arg112* seen in family with congenital diaphragmatic hernia (CDH) and CHD.

 

“Individuals I.1, I.2, II.2, and II.3 underwent exome-sequencing which revealed the p.Arg112* mutation in the ZFPM2 gene in both individuals affected with isolated CDH (II.2 and II.3) as well the asymptomatic mother (I.2). Further analysis of additional family members revealed that the sibling II.4, affected with a TAPVR and anterior diaphragm eventration also shares the mutation which is likely to be responsible for the diaphragm and heart defect.” (1 pt, only counting the individual with CHD)

PMID: 33461977- Frameshift (c.757_761dup) variant seen in individual with congenital diaphragmatic hernia and multiple other congenital anomalies including CHD. (Supplemental table S1 pt 35). Downgrading to 0.5 pts b/c of complexity of the phenotype reported and CHD only part of it. (0.5 pts)

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

PMID: 10888889- Knockout mice showed CHD phenotype (1 pts)

PMID: 10892744- Knockout mice showed CHD phenotype (1 pts)

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

 

Source:

Limited

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Unknown

 

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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