Possible mitochondrial disorder - nuclear genes

Gene: PDE12

Green List (high evidence)

Comment on list classification: 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, 10:07 p.m. | Last Modified: 7 Aug 2025, 10:07 p.m.

Panel Version: 4.8

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.
Sources: Literature

Created: 7 Aug 2025, 10:06 p.m. | Last Modified: 7 Aug 2025, 10:27 p.m.

Panel Version: 4.8

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
mitochondrial disease, MONDO:0044970

Publications

• 39567835