ClinVar

In 4 patients from 3 unrelated families (F1, F2, and F3) with familial erythrocytosis-2 (ECYT2; 263400), Lenglet et al. (2018) identified compound heterozygous mutations in the VHL gene. All 4 patients carried a T-to-C transition (c.340+770T-C) in cryptic exon 1-prime (E1-prime), resulting in a splicing alteration, on 1 allele. Three patients from F2 and F3 had previously been diagnosed with Chuvash polycythemia since they were heterozygous for the R200W mutation (608537.0019) on the other allele. Prior to the study of Lenglet et al. (2018), these patients were thought to carry only 1 VHL mutation (the patient from F2 had previously been reported by Cario et al., 2005). The mutations, which were found by a combination of whole-genome and Sanger sequencing, segregated with the disorder in the families. RT-PCR analysis of lymphoblastoid cells from 1 patient (F1) showed a decrease in the exon 1/exon 2/exon 3 isoform and an increase in an exon 1/exon 3 isoform compared to wildtype. The patient from F1 carried a synonymous c.429C-T transition (asp143-to-asp, D143D) on the other allele, which also affected splicing. Two further unrelated patients with ECYT2 (families F9 and F10) were homozygous for the c.429C-T transition in the VHL gene. RT-PCR analysis from lymphocytes derived from these patients showed decreased mRNA levels, increased amounts of the E1/E3 transcripts, and severe decreases in the wildtype VHL mRNA and protein isoform compared to controls, suggesting that the mutation resulted in the skipping of exon 2. The 2 patients from families F9 and F10 also had mutations in the HBB gene (141900), which may have compensated for the ECYT2.