A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations

Abstract

In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria. For disease gene/mutation identification, multiplex ligation-dependent probe amplification, quantitative PCR, linkage, and Sanger and whole genome sequencing assays were carried out. A total of 116 patients (50 families) were examined. Fifty-four patients (46.55%; 22 families) were found to carry pathogenic mutations in known genes while a novel gene, not previously associated with parkinsonism, was found mutated in a single family (2 patients). Pathogenic mutations, including missense, nonsense, frameshift, and exon rearrangements, were found in Parkin, PINK1, DJ-1, SYNJ1, and VAC14 genes. In conclusion, variable phenotypic expressivity was seen across all families.

VAC14 Gene‐Related Parkinsonism‐Dystonia With Response to Deep Brain Stimulation

“…Mouse models present with neurodegeneration and enlarged endolysosomal vacuoles, recapitulating the neuropathological findings from human subjects . In the few patients reported on so far, age of onset seems to range from 1.5 to 13 years, with onset of dystonia in a limb with rapid generalization affecting gait . Imaging may demonstrate diffusion restriction in the striatum and susceptibility‐weighed hypointensity in the pallidum and SN (Supporting Information Table S2).…”

“…The duplication was thought to be an incidental finding, given mismatch between patient and typical phenotype. Upon reviewing the areas of homozygosity, the VAC14 gene stood out as a potential candidate based on previous reports …”

“…Upon reviewing the areas of homozygosity, the VAC14 gene stood out as a potential candidate based on previous reports. [1][2][3] Sequencing of the VAC14 gene identified a homozygous missense variant of unknown significance (p.Lys651Glu, c.1951A > G). The variant has not been previously described in publicly available databases (gnomAD, Exome Variant Server, or 1000 Genomes) and involves a highly conserved amino acid in the protein C-terminal dimerization domain, where previous pathogenic mutations have been located.…”

Molecular characterization of PRKN structural variations identified through whole‐genome sequencing

“…SVs (exon rearrangements) are the most common type of mutations, being identified in about 43.2% of the reported patients (Kasten, et al, ). In a large multicenter study, where we identified PRKN mutations in 71.42% of the examined patients, SVs were the most prevalent mutations identified in the Iranian PD population (Taghavi et al, ). The most common PRKN SV identified to date in the PD population is the c.(171+1_172‐1)_(412+1_413‐1)del mutation, which consists of a deletion encompassing the entire exon 3 of the PRKN gene (https://www.mdsgene.org) (Kasten, et al, ).…”

SYNJ1 gene associated with neonatal onset of neurodegenerative disorder and intractable seizure

“…Another homozygous mutation R459P in SYNJ1 was identified in an Indian family (Kirola, Behari, Shishir, & Thelma, ). Recently, Taghavi et al., () published a SYNJ1 p.R839C mutation in two Iranian siblings with poorly levodopa‐responsive Parkinsonism and generalized seizures since 24 years of age associated with longitudinal tongue fissures. All affected individuals showed early progressive Parkinsonism symptoms in their twenties in combination with cognitive decline or early‐onset refractory seizures (Krebs et al., ; Olgiati et al., ).…”