Disorders of sex development
Gene: ZFPM2
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
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.
Comment on phenotypes: Also associated with Diaphragmatic hernia 3 610187 and Tetralogy of Fallot 187500Created: 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 casesCreated: 2 Nov 2016, 4:15 p.m.
Comment on list classification: additional variants reportedCreated: 2 Nov 2016, 2:01 p.m.
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
Phenotypes for gene: ZFPM2 were changed from 46XY sex reversal 9 616067 to 46XY sex reversal 9, OMIM:616067
Gene: zfpm2 has been classified as Amber List (Moderate Evidence).
Promoted to V1 21/12/2016
Phenotypes for ZFPM2 were set to 46XY sex reversal 9 616067
This gene has been classified as Green List (High Evidence).
This gene has been classified as Green List (High Evidence).
This gene has been classified as Green List (High Evidence).
Publications for ZFPM2 were set to 24549039; 21919901; 25813279
Publications for ZFPM2 were set to 24549039
This proposed gene was validated and added to this panel
ZFPM2 was added to Disorders of sex developmentpanel. Sources: Other
ZFPM2 was created by John Achermann
ZFPM2 was added to Disorders of sex developmentpanel. Sources: Expert Review