# Rare PANK2 variants and pantothenate-kinase-associated neurodegeneration in the Dominican Republic

## TL;DR

This study identifies rare PANK2 gene variants causing a fatal neurological disorder in an isolated region of the Dominican Republic, revealing a high carrier frequency and a likely African origin of the mutation.

## Contribution

The study identifies a high carrier frequency of a PANK2 variant in the Dominican Republic and confirms a founder effect with African ancestry.

## Key findings

- A PANK2 variant (c.680A > G) was homozygous in 42 of 46 affected individuals, with high heterozygous carrier frequency in the Dominican Republic.
- Haplotype analysis confirmed a founder effect with African origin for the PANK2 mutations.
- Compound heterozygosity was observed in four individuals from two families.

## Abstract

Pantothenate-kinase-associated neurodegeneration (PKAN) is a rare, autosomal recessive neurological disorder characterized by the progressive degeneration of specific regions in the brain and is invariably fatal. Several individuals in families affected by PKAN were known to live in an isolated region in a southwestern province of the Dominican Republic and had been previously studied. Forty-six individuals with PKAN in 34 families were evaluated for disease manifestations using the PKAN-Disease Rating Scale and the Leiter-3 Cognitive and Neuropsychological assessment. We completed whole genome sequencing in the 46 affected individuals and their 80 unaffected relatives. Haplotype analysis was used to identify shared genetic patterns among individuals with the mutation to identify common ancestral and founder effects. The classic form of PKAN was observed in 22 individuals with moderate-to-severe oromandibular dystonia and limb dystonia and onset in early childhood. The atypical form was observed in 24 individuals with Parkinsonism, dystonia, cognitive deficits, and later onset of disease. A PANK2 variant, chr20:3907977: A:G (c.680A  >  G, p.Y227C), was homozygous among 42 affected individuals equally divided by disease form. There were 59 heterozygous carriers of this variant among parents and relatives of the affected individuals. Four individuals from two families were compound heterozygotes for c.680A  >  G and chr20:3918728: C:T (c.1594C  >  T). Haplotype analyses revealed shared patterns across families and of African origin consistent with founder effects for c.680A  >  G and c.1594C  >  T, likely introduced to the island 25–35 generations earlier. The frequency of heterozygous carriers of c.680A  >  G allele among individuals of Dominican ancestry living in New York was 0.18% but was 0.8% among individuals living in the Dominican Republic, significantly higher than the reported frequency for all causal PANK2 mutations worldwide. This investigation confirmed likely founder mutations in PANK2 associated with the classic and atypical forms of PKAN in 34 families in an isolated region of the Dominican Republic. Compound heterozygosity was observed in four individuals from two families. The heterozygous frequency of c.680A  >  G was exceptionally high in the Dominican population compared with worldwide data. Founder mutations in such communities offer a unique opportunity to set up relevant, affordable and accessible genetic counselling and screening.

Vardarajan et al. used whole genome sequencing in 46 individuals with pantothenate-kinase-associated neurodegeneration and 80 unaffected individuals from 34 families to identify causal mutations in the PANK2 gene. A homozygous variant was present in most affected individuals. Haplotype analysis confirmed a founder effect and an African ancestral origin.

Graphical Abstract