Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Approximately 15% of PD patients have a family history of the disease in one or more first-degree relatives, and 5-10% of PD cases exhibit a classical Mendelian inheritance pattern. In 1997, the heritable transmission of PD was first documented. Recent studies have found 90 independent genome-wide signals at 78 loci that may be associated with PD. The identification of genes linked to PD and their functions has uncovered novel biological pathways and treatment options that play a role in the development of PD. In this article, it is aimed to review up-to-date information on the genetics of PD.

Background: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA). Accumulation of sulfatide, substrate of ARSA, in the central and peripheral nervous system causes neurodegeneration, which leads to neurologic and psychiatric symptoms. Adult-onset MLD is the least frequent type of MLD and shows both genetic and clinical heterogeneity. The clinical presentation differs according to pathogenic variants in the ARSA gene. Therefore, establishing genotype–phenotype correlation is crucial for the diagnosis and management of patients with adult-onset MLD. Methods: A family of multiple individuals with adult-onset psychomotor deterioration was assessed. The patients had behavioral disturbances initially, and neurological deficits had developed in the later stages of the disease. The family was analyzed using karyotype analysis, Sanger sequencing, custom next-generation sequencing (NGS) panel of the genes related to dementia, and whole exome sequencing (WES). Results: Karyotype analysis and NGS dementia panel showed no pathogenic aberration. However, WES analysis revealed heterozygous variants in the ARSA gene: c.542T>G (p.Ile181Ser) and c.661T>A (p.Phe221Ile). Segregation analysis, performed by Sanger sequencing, showed that all individuals with the same clinical findings were compound heterozygous for c.542T>G and c.661T>A substitutions. Conclusion: The compound heterozygosity of c.542T>G and c.661T>A variants of the ARSA gene cause adult-onset MLD. The genotype detected in the patients was not reported before in the literature. Moreover, the clinical course of the patients followed a similar pattern with dominantly psychiatric symptoms at the initial stage of the disease, indicating a distinct phenotype caused by the two pathogenic variants of the ARSA gene.

Cholesteatoma is a proliferative disease that affects the tympanic cavity and temporal bone. Despite many studies and various theories, the etiopathogenesis of cholesteatoma has not been fully elucidated. Features such as invasion, migration, uncontrolled proliferation, and lack of differentiation are observed in both cholesteatoma and neoplasia. The aim of this study is to investigate somatic genetic alterations in known proto-oncogenes and tumor suppressor genes in cholesteatoma. 60 different known proto-oncogenes and tumor suppressor genes were comparatively analyzed in cholesteatoma and peripheric blood samples from 15 middle ear cholesteatoma patients using next-generation sequencing. JAK3 c.2164G > A, TP53 c.284delC, and KRAS c.377A > T alterations were observed in cholesteatoma tissue but not in normal tissue. In addition, 12 different germline variants were also identified in 8 patients. In this study, the presence of changes in cancer-related genes in cholesteatoma was determined and these changes were discussed in terms of possible clinical applications. We hope that the genetic alterations that emerged in this study, will be beneficial in guiding future research in this field.