Genetic And Phenotypic Analysis Of Patients With Early-onset Parkinson Disease From Consanguineous Families

BackgroundParkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease. PD occurs as a sporadic disorder in the vast majority of patients. However, the disease, in approximately5%to10%of patients, occurs as a Mendelian disorder. Monogenic forms of PD are inherited in an autosomal dominant or autosomal recessive (ARPD) fashion. Most of ARPD is juvenile onset or early onset. Mutations in Parkin, PINK1and DJ-1are associated with autosomal recessive typical parkinsonism. Mutations in ATP13A2, FBXO7, PLA2G6, DNAJC6and SYNJ1are associated with autosomal recessive atypical parkinsonism.Consanguinity increases the coefficient of inbreeding. By mating with a close kin, offspring of consanguineous families inherit a large number of genetic materials from the same ancestor. Although this is known to have an adverse outcome by increasing the risk of autosomal recessive disorders, this phenomenon has also been exploited for genetic analysis. Consanguineous families are very useful material to research autosomal-recessive disease. In recent2years, we collected a cohort of patients with early onset Parkinson disease from11consanguineous families. This study intends to perform genetic analysis by using these families.Objective(1) To establish a rapid, efficient method to detect the mutations of patients with early onset Parkinson disease (EOPD) from consanguineous families.(2) To detect the mutations of patients with EOPD and analyze genotype-phenotype relationships.(3) To screen candidate consanguineous families in which patients with EOPD may be caused by new causative genes. These families could be used to clone new causative gene of ARPDMethodsWe recruited a cohort of patients with EOPD from11consanguineous families. All participants underwent a detailed neurological examination. The coding sequences of the Parkin cDNA of probands in11families were amplified by PCR amplification and PCR products were purified and directly sequenced to detect mutations in Parkin. Homozygosity mapping and Sanger sequencing were used to identify the causative mutation for families without Parkin mutations. Genotype-phenotype relationship was detailed analyzed.ResultsFour homozygous Parkin CNV mutations (exon4, exon8-9, exon7, exon3-4deletion) in4families and one homozygous point mutation of c.G991T (p.D331Y) in PLA2G6in2families were identified by homozygosity mapping and Sanger sequencing. One homozygous point variation of c.1489A>G (p.497R>G) in PINK1 was identified in one family. In silico analysis indicated the c.1489A>G variation is a disease causing mutation. Patients with PLA2G6p.D331Y mutation manifest pure early-onset parkinsonism, in line with the fourth phenotype of PLA2G6-associated neurodegeneration.Conclusion(1) We establish a rapid, efficient method to detect the mutations of patients with EOPD from consanguineous families.(2) Our finding provides further evidence that pure EOPD is the fourth phenotype of PLA2G6-associated neurodegeneration.(3) We identified6mutations of patients with EOPD in6consanguineous families and found a probable diseasing causing variation in one family.(4) We found4consanguineous families in which patients were probable caused by new causative genes. These families could be used to clone new causative gene of ARPD...