PTRHD1 Loss‐of‐function mutation in an african family with juvenile‐onset Parkinsonism and intellectual disability

ABSTRACT Background: The genetic bases of PD in sub‐Saharan African (SSA) populations remain poorly characterized, and analysis of SSA families with PD might lead to the discovery of novel disease‐related genes. Objectives: To investigate the clinical features and identify the disease‐causing gene in a black South African family with 3 members affected by juvenile‐onset parkinsonism and intellectual disability. Methods: Clinical evaluation, neuroimaging studies, whole‐exome sequencing, homozygosity mapping, two‐point linkage analysis, and Sanger sequencing of candidate variants. Result: A homozygous 28‐nucleotide frameshift deletion in the PTRHD1 coding region was identified in the 3 affected family members and linked to the disease with genome‐wide significant evidence. PTRHD1 was recently nominated as the disease‐causing gene in two Iranian families, each containing 2 siblings with similar phenotypes and homozygous missense mutations. Conclusion: Together with the previous reports, we provide conclusive evidence that loss‐of‐function mutations in PTRHD1 cause autosomal‐recessive juvenile parkinsonism and intellectual disability. © 2018 International Parkinson and Movement Disorder Society