Biallelic PTRHD1 Frameshift Variants Associated with Intellectual Disability, Spasticity, and Parkinsonism

Background PTRHD1 was proposed as a disease-causing gene of intellectual disability, spasticity, and parkinsonism. Objectives To characterize the clinical phenotype and the molecular cause of intellectual disability in four affected individuals of a consanguineous family. Methods Clinical evaluation, whole-exome sequencing, Sanger sequencing, reverse transcription polymerase chain reaction (PCR), real-time PCR, immunoblot, and isoelectric focusing. Results A homozygous 28-nucleotide frameshift deletion introducing a premature stop codon in the PTRHD1 exon 1 was identified in the four affected members. We further confirmed the apparent transcript escape of the nonsense-mediated messenger RNA (mRNA) decay pathway. Real-time PCR showed that mRNA expression of the mutant PTRHD1 is higher compared to the wild-type. Western blotting and isoelectric focusing identified a truncated, but stable mutant PTRHD1 protein expressed in the patient's primary cells. Conclusions We provide further evidence that PTRHD1 mutations are associated with autosomal-recessive childhood-onset intellectual disability associated with spasticity and parkinsonism.