Copy number analysis from whole-exome sequencing data revealed a novel homozygous deletion in PARK7 leads to severe early-onset Parkinson's disease.

Parkinson's disease (PD), a neurodegenerative disease characterized by both motor neuron and non-motor neuron symptoms, is the most frequent neurodegenerative disease after Alzheimer's disease. Both genetic and environmental factors take part in disease etiology. Most cases are considered complex multifactorial diseases. About 15% of PD appear in the familial form, and about 5% of all cases arise from a single gene mutation. Among Mendelian causes of PD, PARK7 is one of the autosomal recessive forms due to loss-of-function mutations in both gene alleles. Both single nucleotide variants (SNVs) and copy number variations (CNVs) are observed in PARK7. This study presents an Iranian family with familial PD where some relatives had psychiatric disorders. A homozygous 1617 bp deletion in a female with early-onset PD was detected through copy-number analysis from whole-exome sequencing (WES) data in this consanguineous family. Further investigation by surveying microhomology revealed that the actual size of the deletion is 3,625 bp. This novel CNV that was in the PARK7gene is supposed to co-relation with early-onset PD and infertility in this family.

Whole-Exome Sequencing Study of Consanguineous Parkinson's Disease Families and Related Phenotypes: Report of Twelve Novel Variants.

Parkinson's disease (PD) is a common progressive neurodegenerative disorder with motor and nonmotor symptoms. Recent studies demonstrate various susceptibility loci and candidate genes for familial forms of the disease. However, the genetic basis of the familial form of early-onset PD (EOPD) is not widely studied in the Iranian population. Therefore, the present study aimed to investigate the possible causative genetic variants responsible for developing EOPD among Iranian patients. Iranian patients with a clinical diagnosis of Parkinson's disease were evaluated, and 12 consanguineous families with at least two affected individuals with early-onset PD (EOPD) were chosen to enroll in the present study. An expert neurologist group examined these families. Whole-exome sequencing (WES) was performed on PD patients, and the possible causative genetic variants related to the development of PD were reported. Exome sequencing (WES) was performed on every PD patient and revealed that patients had novel genetic variants in PRKN, PARK7, and PINK1 genes. All the genetic variants were in homozygous status and none of these variants were previously reported in the literature. Moreover, these genetic variants were "pathogenic" based on bioinformatic studies and according to the American College of Medical Genetics (ACMG). The present research revealed some novel variants for EOPD among the Iranian population. Further functional studies are warranted to confirm the pathogenicity of these novel variants and establish their clinical application for the early diagnosis of EOPD.

Lack of Association between Genetic Risk Loci for Restless Legs Syndrome and Multimorbidity.

STUDY OBJECTIVES: Multimorbidity is a risk factor for incident restless legs syndrome (RLS). In this relationship, the potential role of known genetic risk loci for RLS has not been studied. Our aim was to evaluate whether carriers of specific RLS risk alleles have higher comorbidity burden than noncarriers. METHODS: The Dortmund Health Study (DHS) and the Study of Health in Pomerania (SHIP) are two independent cohort studies in Germany based on age-stratified, random samples drawn from the respective population registers. DHS included 1,312 subjects and SHIP included 4,308 subjects. RLS status was assessed according to the RLS standard minimal criteria. A comorbidity index was calculated by summing the scores of the following conditions: diabetes, hypertension, myocardial infarction, obesity, stroke, cancer, renal disease, anemia, depression, thyroid disease, and migraine. Thirteen single nucleotide polymorphisms (SNP) previously associated with elevated risk of RLS were genotyped. Analyses were carried out on the pooled sample of the two studies. RESULTS: The mean age was 50.4 ± 15.9 y, and the proportion of women was 51.4%. The mean number of comorbid conditions was 1.5 ± 1.3. In multivariable regression, the mean number of comorbidities was not significantly different between carriers of any of the RLS risk alleles and noncarriers either in the total pooled sample or in those having RLS symptoms. CONCLUSIONS: Based on these results it is unlikely that known genetic risk factors for RLS would lead to increased multimorbidity.