Optic neuropathy

Gene: PPIB

Green List (high evidence)

Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - possibly a variant-specific phenotype.

Created: 28 Oct 2025, 4:32 p.m. | Last Modified: 25 Jun 2026, 8:50 a.m.

Panel Version: 6.43

PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.

PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026). The gene is Amber on the Optic atrophy panel in PanelApp Australia, and it has not been curated in ClinGen or Gene2Phenotype.

Created: 28 Oct 2025, 4:24 p.m. | Last Modified: 25 Jun 2026, 8:52 a.m.

Panel Version: 6.43

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
optic atrophy, MONDO:0003608

Publications

• 21282188
• 41045073