Differences in sex development

Gene: ZFPM2

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

• 24549039
• 27899157
• 12223418

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.

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.

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

• 24549039