1. Panels
  2. Fetal anomalies
  3. PDE12
Genes in panel
Prev Next

Fetal anomalies

Gene: PDE12

Amber List (moderate evidence)
PDE12 (phosphodiesterase 12)
EnsemblGeneIds (GRCh38): ENSG00000174840
EnsemblGeneIds (GRCh37): ENSG00000174840
OMIM: 616519, Gene2Phenotype
PDE12 is in 4 panels

3 reviews

Arina Puzriakova (Genomics England Curator)

I don't know

Maintaining Amber rating following further consultation with the expert group - The concern is that the two prenatal presentations are very different. There is no link between brain anomalies and hydrops. The panel want to see more evidence that the gene is causing a prenatal phenotype and there is not another cause of these abnormalities in these families.
Created: 26 Sep 2025, 2:59 p.m. | Last Modified: 26 Sep 2025, 2:59 p.m.
Panel Version: 6.86
Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group. However, tagging for additional expert review to resolve conflicting reviews - first reviewed as Green by Achchuthan Shanmugasundram but then as Amber by Alice Gardham based on the same evidence.
Created: 5 Sep 2025, 4:41 p.m. | Last Modified: 8 Sep 2025, 4:06 p.m.
Panel Version: 6.82
Created: 5 Sep 2025, 4:41 p.m.
Last Modified: 8 Sep 2025, 4:06 p.m.
Panel version: 6.86

Alice Gardham (North West Thames Genetics)

I don't know

This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Created: 5 Sep 2025, 4:31 p.m. | Last Modified: 5 Sep 2025, 4:31 p.m.
Panel Version: 6.28
mitochondrial disorder. 3 families. Family 1 -nil prenatal. Family 2 -one neonatal presentation with lissencephaly, dysgenesis of the corpus callosum and extensive periventricular and subcortical cysts. Family 3 -two babies affected. increased nuchal translucency, later severe intra-uterine growth retardation, hydrops and cystic hygroma, talipes, ?vermis rotation. This pregnancy ended spontaneously. At 13 weeks of the next pregnancy nuchal translucency (14?mm) and the absence of foetal movements, contractures. Cell studies.
Created: 5 Sep 2025, 2:55 p.m. | Last Modified: 5 Sep 2025, 2:55 p.m.
Panel Version: 6.24

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial disease, MONDO:0044970

Publications

Created: 5 Sep 2025, 2:55 p.m.
Last Modified: 5 Sep 2025, 2:55 p.m.
Panel version: 6.28

Achchuthan Shanmugasundram (Genomics England Curator)

I don't know

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GMS reviewers commented as follows: The concern from the panel for this one is that the two prenatal presentations are very different. There is no link between brain anomalies and hydrops. The panel want to see more evidence that the gene is causing a prenatal pehnotype and there is not another cuase of these abnormalities in these families.
Created: 12 Dec 2025, 3:10 p.m. | Last Modified: 12 Dec 2025, 3:10 p.m.
Panel Version: 6.120
Comment on list classification: Of the three unrelated families reported with biallelic PDE12 variants, foetal anomalies were reported in two families. There is also functional and in silico evidence available. Hence, this gene can be promoted to green rating in the next GMS update.
Created: 7 Aug 2025, 10:25 p.m. | Last Modified: 7 Aug 2025, 10:25 p.m.
Panel Version: 6.15
PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis.

Of these, the patient from family 2 (died on day 2 after birth), and the two foetuses from family 3 had foetal anomalies detected via prenatal ultrasound. The patient from family 2 had brain anomalies. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses from family 3 and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks.

All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population.

Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Created: 7 Aug 2025, 10:06 p.m. | Last Modified: 7 Aug 2025, 10:22 p.m.
Panel Version: 6.14

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
mitochondrial disease, MONDO:0044970

Publications

Created: 7 Aug 2025, 10:06 p.m.
Last Modified: 7 Aug 2025, 10:22 p.m.
Panel version: 6.120

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • mitochondrial disease, MONDO:0044970
  • Mitochondrial disease, MONDO:0044970
OMIM
616519
Clinvar variants
Variants in PDE12
Penetrance
None
Publications
Panels with this gene

History Filter Activity

26 Sep 2025, Gel status: 2

Removed Tag, Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_25_promote_green was removed from gene: PDE12. Tag Q3_25_expert_review was removed from gene: PDE12.

8 Sep 2025, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_25_expert_review tag was added to gene: PDE12.

5 Sep 2025, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Added phenotypes Mitochondrial disease, MONDO:0044970 for gene: PDE12

7 Aug 2025, Gel status: 2

Entity classified by Genomics England curator

Achchuthan Shanmugasundram (Genomics England Curator)

Gene: pde12 has been classified as Amber List (Moderate Evidence).

7 Aug 2025, Gel status: 1

Created, Added New Source, Added Tag, Set mode of inheritance, Set publications, Set Phenotypes

Achchuthan Shanmugasundram (Genomics England Curator)

gene: PDE12 was added gene: PDE12 was added to Fetal anomalies. Sources: Literature Q3_25_promote_green tags were added to gene: PDE12. Mode of inheritance for gene: PDE12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE12 were set to 39567835 Phenotypes for gene: PDE12 were set to mitochondrial disease, MONDO:0044970 Review for gene: PDE12 was set to GREEN