Mitochondrial disorders

Gene: PDE12

Green List (high evidence)

Comment on list classification: As reviewed by Karen Stals, there is sufficient evidence (three unrelated families and functional evidence) available for the association of biallelic variants in this gene with mitochondrial disease. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 7 Aug 2025, 10:03 p.m. | Last Modified: 7 Aug 2025, 10:03 p.m.

Panel Version: 9.23

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.

In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses from family 3 by prenatal ultrasound 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.

Created: 7 Aug 2025, 9:59 p.m. | Last Modified: 7 Aug 2025, 10:21 p.m.

Panel Version: 9.23

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
mitochondrial disease, MONDO:0044970

Publications

• 39567835

Green List (high evidence)

Disease-causing PDE12 variants identified in three unrelated families associated with mitochondrial respiratory chain deficiencies and 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. Whole exome sequencing of affected probands revealed novel, segregating bi-allelic missense PDE12 variants affecting conserved residues (PMID:39567835).

Created: 30 Jul 2025, 12:15 p.m. | Last Modified: 30 Jul 2025, 12:15 p.m.

Panel Version: 9.19

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neonatal mitochondrial disease

Publications

• PMID:39567835

Red List (low evidence)

Not associated with phenotype in OMIM or in Gen2Phen. PDE12 is involved in a deadenylation-dependent mtRNA maturation pathway in human mitochondria (PMID 28745585).

Created: 5 Aug 2019, 10:38 a.m. | Last Modified: 5 Aug 2019, 10:38 a.m.

Panel Version: 1.423

Publications

• 29903433
• 28745585