PNPLA6 – Oliver-McFarlane Syndrome

Oliver-McFarlane syndrome (OMCS) is a rare autosomal recessive disorder characterized by congenital trichomegaly, chorioretinal degeneration, anterior hypopituitarism and profound growth retardation. Affected infants present with hair anomalies, pituitary hormone deficiencies leading to dwarfism, and early-onset retinopathy with choroidal atrophy, often accompanied by neurodevelopmental delay.

Biallelic PNPLA6 variants underlie OMCS. To date, over 30 unrelated OMCS probands have been reported in more than 14 families with confirmation of autosomal recessive inheritance and consistent segregation (PMID:32758583, PMID:33818269). The spectrum includes missense, nonsense, frameshift and splice site mutations, with most clustering in the phospholipid esterase domain.

Variant spectrum analysis across OMCS cases reveals recurrent and novel alleles. For example, the compound heterozygous c.1491G>T (p.Glu497Asp) variant disrupts a conserved residue in the esterase domain and was identified in the 14th reported case (PMID:32758583). No clear founder mutations have emerged, and alleles are private to single families.

Extensive functional studies support a loss-of-function mechanism. Zebrafish pnpla6 morphants are rescued by wild-type human PNPLA6 mRNA but not by mutant transcripts (PMID:25480986). In Drosophila, disease-associated PNPLA6 variants fail to restore normal lipid homeostasis despite partial behavioral rescue (PMID:31780887). An allelic mouse series demonstrates an NTE activity threshold for retinopathy that mirrors the human genotype:activity:phenotype relationship (PMID:38735647).

No studies have refuted the PNPLA6–OMCS association, and alternative genetic etiologies have not been reported in well-characterized OMCS cohorts. The consistent clinical spectrum across consanguineous and non-consanguineous families, combined with robust animal model concordance, reinforces the gene-disease link.

Integrating genetic and experimental data, PNPLA6 meets criteria for a Definitive gene-disease association. Genetic testing for PNPLA6 variants is essential for confirmation of OMCS, guiding endocrine management, ophthalmologic surveillance, and family counselling. Key Take-home: Biallelic PNPLA6 loss-of-function variants cause Oliver-McFarlane syndrome, and NTE activity assays may inform prognosis and therapeutic development.

References

• Gene • 2020 • Identification of Oliver-McFarlane syndrome caused by novel compound heterozygous variants of PNPLA6. PMID:32758583
• Ophthalmic genetics • 2021 • Oliver McFarlane syndrome: two new cases and a review of the literature. PMID:33818269
• Journal of medical genetics • 2015 • Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. PMID:25480986
• Frontiers in neuroscience • 2019 • Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila. PMID:31780887
• Brain: a journal of neurology • 2024 • Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders. PMID:38735647

Evidence Based Scoring (AI generated)