Rare <i>PANK2</i> variants and pantothenate-kinase-associated neurodegeneration in the Dominican Republic

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 <i>PANK2</i> variant, chr20:3907977: A:G <i>(c.680A</i> <i>></i> <i>G, p.Y227C),</i> 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 <i>c.680A</i> <i>></i> <i>G</i> and chr20:3918728: C:T (<i>c.1594C</i> <i>></i> <i>T).</i> Haplotype analyses revealed shared patterns across families and of African origin consistent with founder effects for <i>c.680A</i> <i>></i> <i>G</i> and <i>c.1594C</i> <i>></i> <i>T</i>, likely introduced to the island 25-35 generations earlier. The frequency of heterozygous carriers of <i>c.680A</i> <i>></i> <i>G</i> 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 <i>PANK2</i> mutations worldwide. This investigation confirmed likely founder mutations in <i>PANK2</i> 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 <i>c.680A</i> <i>></i> <i>G</i> 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.