Disorders of sex development

Gene: ZFPM2

Amber List (moderate evidence)

ZFPM2 (zinc finger protein, FOG family member 2)
EnsemblGeneIds (GRCh38): ENSG00000169946
EnsemblGeneIds (GRCh37): ENSG00000169946
OMIM: 603693, Gene2Phenotype
ZFPM2 is in 4 panels

4 reviews

Martina Owens (Exeter Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust)

I don't know

Bashamboo et al (PMID 24549039) reported 2 cases: case 1 had complete gonadal dysgenesis and a maternally inherited missense variant, case 2 had partial gonadal dysgenesis and a de novo missense variant but was also homozygous for a further missense variant inherited from parents heterozygous for the variant. Functional analysis demonstrated impaired ability of the mutant ZFPM2/FOG2 proteins to interact with GATA4, a known regulator of early testis development. Tevosian et al (PMID 12223418) showed mouse fetuses homozygous for a null allele of Fog2, or homozygous for a targeted mutation in Gata4 (Gata4(ki)) that abrogates the interaction of GATA4 with FOG co-factors, exhibit abnormalities in gonadogenesis. Eggers et al (PMID 27899157) reported 10 different variants in 10 patients with 46,XY gonadal dysgenesis, however, 7 of the variants are common in gnomAD (≥0.1%) and we would classify the remainder as variants of uncertain significance. Using the ClinGen framework to evaluate relevant genetic and experimental evidence for gene-disease association gives a qualitative classification of ‘Limited’ (PMID 28552198). Therefore I recommend that this gene should be downgraded to Amber.
Created: 8 Jul 2019, 10:55 a.m. | Last Modified: 8 Jul 2019, 10:55 a.m.
Panel Version: 1.35

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
46XY sex reversal 9 616067

Publications

Ivone Leong (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Demoted from green to amber based on the evidence provided by Martina Owens (Exeter Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust).
Created: 10 Jul 2019, 9:09 a.m. | Last Modified: 10 Jul 2019, 9:09 a.m.
Panel Version: 1.36
As discussed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019: The Specialist Test Group agreed that there is enough evidence to rate this gene green.
Created: 29 Apr 2019, 9:46 a.m.

Sarah Leigh (Genomics England Curator)

Comment on phenotypes: Also associated with Diaphragmatic hernia 3 610187 and Tetralogy of Fallot 187500
Created: 3 Nov 2016, 10:24 a.m.
Comment when marking as ready: Associated with phenotype in OMIM, not in G2P / DD. At least three variants reported in four cases
Created: 2 Nov 2016, 4:15 p.m.
Comment on list classification: additional variants reported
Created: 2 Nov 2016, 2:01 p.m.

John Achermann (UCL Institute of Child Health)

Red List (low evidence)

Partner protein of GATA4. May have testicular dysgenesis and heart defects. Only single report so far.
Created: 4 Feb 2016, 4:25 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Other
Phenotypes
  • 46XY sex reversal 9 616067
OMIM
603693
Clinvar variants
Variants in ZFPM2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

10 Jul 2019, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: zfpm2 has been classified as Amber List (Moderate Evidence).

21 Dec 2016, Gel status: 4

panel promoted to version 1

Sarah Leigh (Genomics England Curator)

Promoted to V1 21/12/2016

3 Nov 2016, Gel status: 4

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for ZFPM2 were set to 46XY sex reversal 9 616067

2 Nov 2016, Gel status: 4

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

2 Nov 2016, Gel status: 4

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

2 Nov 2016, Gel status: 4

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

2 Nov 2016, Gel status: 0

Set publications

Sarah Leigh (Genomics England Curator)

Publications for ZFPM2 were set to 24549039; 21919901; 25813279

2 Nov 2016, Gel status: 0

Set publications

Sarah Leigh (Genomics England Curator)

Publications for ZFPM2 were set to 24549039

23 May 2016, Gel status: 0

Approved Gene

Sarah Leigh (Genomics England Curator)

This proposed gene was validated and added to this panel

23 May 2016, Gel status: 0

Upload gene information

Sarah Leigh (Genomics England Curator)

ZFPM2 was added to Disorders of sex developmentpanel. Sources: Other

4 Feb 2016, Gel status: 0

Created

John Achermann (UCL Institute of Child Health)

ZFPM2 was created by John Achermann

4 Feb 2016, Gel status: 0

Added New Source

John Achermann (UCL Institute of Child Health)

ZFPM2 was added to Disorders of sex developmentpanel. Sources: Expert Review