ClinVar

In affected members of a large multigenerational consanguineous Costa Rican family with Charcot-Marie-Tooth disease type 2B2 (CMT2B2; 605589), originally reported by Leal et al. (2001), Leal et al. (2018) identified a homozygous c.1549C-T transition in the last exon (exon 17) of the PNKP gene, resulting in a gln517-to-ter (Q517X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant has a low frequency in the gnomAD database (18 of 245,644 alleles). Previously, the disorder in this family was erroneously attributed to a homozygous variant in the MED25 gene (A335V; 610197.0001), which maps to the same region as PNKP. The MED25 and PNKP variants both fully segregated with the disorder in the family and were shown to be present on the same haplotype, suggesting an ancestral founder haplotype. Analysis of the PNKP coding sequencing in 5 additional Costa Rican probands with a similar phenotype showed that all were compound heterozygous for the Q517X mutation and a Thr408del (605610.0007) mutation. These patients also carried the ancestral haplotype with the MED25 variant. Molecular modeling predicted a damaging effect for the Q517X mutation, although functional studies and studies of patient cells were not performed. Leal et al. (2018) concluded that the mutant protein would lack an important functional C-terminal domain, causing increased DNA damage with subsequent cell death.