Beyond the phenotype: Exploring inherited retinal diseases with targeted next-generation sequencing in a Turkish cohort.

This research aims to compile recent clinical and genetic data from Turkish patients with inherited retinal disorders and evaluate the effectiveness of targeted Next-generation sequencing panels. The study included Turkish individuals with hereditary retinal diseases who visited the Medical Genetic Department of Erciyes University between 2019 and 2022. One proband per family was selected based on eligibility. We used Hereditary Disorder Solution (HDS) by Sophia Genetics and performed next-generation sequencing (NGS) with Illumina NextSeq-500. Bioinformatics analysis using Sophia DDM® SaaS algorithms and ACMG guidelines classified genomic changes. The study involved 354 probands. Disease-causing variants were found in 58.1% of patients, with ABCA4, USH2A, RDH12, and EYS being the most frequently implicated genes. Forty-eight novel variants were detected. This study enhances the knowledge of clinical diagnoses, symptom onset, inheritance patterns, and genetic details for Turkish individuals with hereditary retinal disease. It contributes to broader health strategies by enabling comparisons with other studies.

ABCA4 variant screening in a Turkish cohort with Stargardt disease.

PURPOSE: This study aims to evaluate the ABCA4 variants in patients diagnosed with Stargardt disease. METHODS: This is a retrospective study designed to investigate variants in the ABCA4 in Stargardt disease and the clinical findings of the cases. Sex, age, age of onset of symptoms, best-corrected visual acuity, color fundus photography, optical coherence tomography, and visual field test of the patients were recorded. Genetic analyses were screened, and patients with at least two variants in the ABCA4 were included in this study. RESULTS: Twenty-seven patients diagnosed with Stargardt disease with the ABCA4 variants were included in this study. Twelve of them (44.4%) were female and fifteen (55.5%) were male. The mean age of the cases was 27.44 years (ranging from 8 to 56 years). Thirty different variants were detected in 54 ABCA4 alleles of 27 patients. The two most common pathogenic variants were c.5882 G>A p.(Gly1961Glu) and c.52C>T p.(Arg18Trp) in this cohort. Two novel variants were identified (c.3855_3856dup, c.1554 + 3_1554 + 4del) and the patient with the c.1554 + 3_1554 + 4del variant additionally had a different ABCA4 variant in trans. The other novel variant was homozygous. CONCLUSIONS: In this study, two novel variants were described in a Turkish cohort with Stargardt disease. The variant c.52C>T p.(Arg18Trp) was the most common disease-causing variant besides the c.5882 G>A p.(Gly1961Glu) which was identified frequently in the previous studies. A larger sample size is necessary for describing different pathogenic variants and understanding the phenotype-genotype correlations.

Identifying variants and their pathogenicity in inherited diseases is important for widening the disease-causing mutations and future treatment options.Two novel variants (c.3855_3856dup, c.5910_5912dup) were described in a cohort with Stargardt disease.The most common variants could be different in ethnic groups.The variant c.52C>T p.(Arg18Trp) was the most common variant besides the c.5882G>A p.(Gly1961Glu) which was frequently identified in the previous studies.Describing different pathogenic variants and clinical findings of the patients is important for understanding the phenotype-genotype correlations.

Evaluation of chromosomal abnormalities in the postnatal cohort: A single-center study on 14,242 patients.

BACKGROUND AND AIM: Chromosomal analysis is a laboratory technique used to examine the chromosomes of an individual, offering insights into chromosome numbers, structures, and arrangements to diagnose and comprehend genetic diseases. This retrospective study provides a comprehensive understanding of the distribution by indications in a large cohort of 14,242 patients and the frequency of chromosomal abnormalities in different clinical populations. METHOD: The study examined various indications for karyotype evaluation, with recurrent pregnancy loss being the most common indication, followed by intellectual disability, dysmorphic features, congenital anomalies, and developmental delay. RESULTS: The overall chromosomal abnormality rate was found to be 5.4%, with numerical abnormalities accounting for the majority of cases (61.7%). Trisomies, particularly trisomy 21, were the most frequent numerical abnormalities. In terms of structural abnormalities, inversions and translocations were the most commonly identified. The rates of chromosomal anomalies varied in specific indications such as amenorrhea, disorders of sex development, and Turner syndrome. The study also highlighted significant differences between males and females in the presence of chromosomal abnormalities across certain indications. Males exhibited a higher incidence of chromosomal abnormalities in cases of Down syndrome and infertility, whereas females showed higher abnormalities in terms of recurrent pregnancy loss. CONCLUSION: While this study provides valuable insights into the frequency and distribution of chromosomal abnormalities, it has limitations, including its retrospective design and reliance on data from a single medical genetics department. Nevertheless, the findings emphasize the importance of karyotype analysis in diagnosing chromosomal disorders and providing appropriate management, while also pointing to potential gender-related variations in chromosomal abnormalities that warrant further investigation.

PPM1K defects cause mild maple syrup urine disease: The second case in the literature.

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by the insufficient catabolism of branched-chain amino acids. BCKDHA, BCKDHB, DBT, and DLD encode the subunits of the branched-chain α-ketoacid dehydrogenase complex, which is responsible for the catabolism of these amino acids. Biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT are characteristic of MSUD. In addition, a patient with a PPM1K defect was previously reported. PPM1K dephosphorylates and activates the enzyme complex. We report a patient with MSUD with mild findings and elevated BCAA levels carrying a novel homozygous start-loss variant in PPM1K. Our study offers further evidence that PPM1K variants cause mild MSUD.

Prolidase activity in aqueous and serum samples of cataract cases with Pseudoexfoliation syndrome.

Pseudoexfoliation syndrome (PEX) represents an age-related systemic disease that is characterized by the accumulation of extracellular matrix material in ocular tissues and visceral organs. Abnormal matrix remodeling is thought to be one of the important factors in the etiopathogenesis of the disease. Prolidase represents an enzyme, which takes a significant part in collagen biosynthesis and remodeling of the extracellular matrix. The purpose of the current research was to assess the prolidase enzyme activity in the aqueous and serum samples of subjects with PEX. The study population consisted of 66 subjects, involving 33 subjects with age-related cataract among patients with PEX and 33 subjects with age-related cataract without PEX. The prolidase activity measurement was performed using the modified Chinard's method. Significantly increased aqueous prolidase activity was detected in the group with PEX (p < 0.01). Despite about a three times higher increase in the serum prolidase activity of the group with PEX in comparison with the control group, the two groups did not differ statistically significantly (p > 0.05). The high prolidase enzyme activity in the aqueous samples of subjects with PEX suggests that the collagen cycle and the remodeling of the extracellular matrix are accelerated. These results can be a guide for understanding the formation mechanisms of PEX.

Ophthalmic drugs: in vitro paraoxonase 1 inhibition and molecular docking studies.

Glaucoma is a neuropathy disorder and is generally treated by drugs. Allergic conjunctivitis is a common ophthalmologic disease. Paraoxonase 1 (PON1) is an organophosphate hydrolyzer and antiatherogenic enzyme. PON1 is known for preventing atherosclerosis through lipid-modifying features, as well as which has decisive actions of antiapoptosis, anti-inflammatory, antithrombosis, and antiadhesion antioxidant activity properties. Thus, reducing the enzyme levels in hyperthyroidism, chronic renal failure, glaucoma, diabetes mellitus, and cardiovascular diseases is a significant risk. This study was tested some ophthalmic drugs used to treat the diseases, such as glaucoma and allergic conjunctivitis, mentioned above, travoprost, latanoprost, ketotifen, emedastine, and olopatadine, for their inhibition activities against PON1. These drugs displayed the potent inhibition effect with IC50 values ranging between 14.95 ± 0.15 and 299.60 ± 4.07 µM and KI constants ranging from 9.71 ± 2.63 to 261.50 ± 59.98 µM. Besides, the molecular docking analyses of the competitive inhibitors, travoprost, emedastine, and olopatadine, were performed to understand the binding interactions on the enzyme's binding site. According to both in vitro and in silico analysis results, travoprost had the most potent effect on PON1 enzyme activity.

The effect of brimonidine and proparacaine on metabolic enzymes: Glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and glutathione reductase.

Oxidative stress is to upregulate the pentose phosphate pathway (PPP). The PPP consists of two functional branches, glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconaste dehydrogenase (6PGD). Glutathione reductase (GR) has a significant role in catalyzing an oxidized glutathione form into a reduced form. The purpose of this study is to investigate the effects of brimonidine and proparacaine on the activity of 6PGD, G6PD, and GR enzymes purified from human erythrocytes. Brimonidine displayed considerable inhibition profile against G6PD with IC50 value and KI constant of 29.93 ± 3.56 and 48.46 ± 0.66 µM, respectively. On the other hand, proparacaine had no inhibitory effect against G6PD. KI values were found to be 66.06 ± 0.78 and 811.50 ± 11.13 µM for brimonidine and proparacaine, respectively, for 6PGD. KI values were found to be 144.10 ± 2.01 and 1,654.00 ± 26.29 µM for brimonidine and proparacaine, respectively, for GR. Herein, also in silico molecular docking studies were performed between drugs and enzymes.