The impact of the coronavirus disease 2019 (COVID-19) pandemic has been unceasingly ongoing worldwide. Recent bioinformatics analysis and epidemiologic studies have highlighted that the functional polymorphisms on the angiotensin converting enzyme (ACE) gene may have an impact on the clinical progress of COVID-19. In this study, we aimed to determine the impact of the ACE1 gene I/D polymorphism and ACE2 peptidase-2 domain variants on disease severity. Hundred patients with confirmed COVID-19 related pneumonia [50 patients with severe disease in intensive care unit (ICU) and 50 patients not in ICU] were compared on the basis of genetic and clinical characteristics. Genomic DNA was purified from peripheral blood lymphocytes with an automated QIA symphony DSP DNA Mini-Kit. The Sanger sequencing analysis was performed. The frequencies of ACE1 gene polymorphism and ACE2 PD variants were compared in patients hospitalized in ICU and those not in ICU. The Statistical Package for Social Sciences version 22.0 was used for statistical analysis. The sequencing analysis of the ACE2 gene exon 1 and 2 revealed none of the polymorphisms investigated or any other variants in the present cohort. The frequencies of the ACE1 ID, DD, and II genotypes were 51%, 31%, and 18%, respectively. The frequency of the D allele was similar between the ICU and non-ICU groups (50.4% versus 49.6%). Older age and the presence of advanced stage radiologic abnormalities on admission were detected as independent predictors of ICU requirement. No effect of any ACE1 gene polymorphism on predicting ICU requirement was detected. To the best of our knowledge, this is the first study investigating the impact of ACE gene polymorphisms on clinical severity of COVID-19 in a Turkish cohort.

Charcot-Marie-Tooth disease covers a group of inherited peripheral neuropathies. The aim of this study was to investigate the effect of targeted next-generation sequencing panels on the molecular diagnosis of Charcot-Marie-Tooth disease and its subtypes in routine clinical practice, and also to show the limitations and importance of next-generation sequencing in the diagnosis of Charcot-Marie-Tooth diseases. This is a retrospective study. Three different molecular methods (multiplex ligation probe amplification, next-generation sequencing, and whole-exome sequencing) were used to detect the mutations related to Charcot-Marie-Tooth disease. In total, 64 patients (33 males and 31 females) with suspected Charcot-Marie-Tooth disease were analyzed for molecular etiology. In all, 25 (39%) patients were diagnosed by multiplex ligation probe amplification. With an extra 11 patients with normal PMP22 multiplex ligation probe amplification results that were consulted to our laboratory for further genetic analysis, a total of 50 patients underwent next-generation sequencing for targeted gene panels associated with Charcot-Marie-Tooth disease. Notably, 18 (36%) patients had pathogenic/likely pathogenic variants. Whole-exome sequencing was performed on five patients with normal next-generation sequencing results; the diagnostic yield by whole-exome sequencing was 80% and it was higher in the childhood group. The molecular etiology in Charcot-Marie-Tooth disease patients can be determined according to pre-test evaluation, deciding the inheritance type with pedigree analysis, the clinical phenotype, and an algorithm for the genetic analysis. The presence of patients without a molecular diagnosis in all the literature suggests that there are new genes or mechanisms waiting to be discovered in the etiology of Charcot-Marie-Tooth disease.

As a major component of intracellular trafficking, the coat protein complex II (COPII) is indispensable for cellular function during embryonic development and throughout life. The 4 SEC24 proteins (A–D) are essential COPII components involved in cargo selection and packaging. A human disorder corresponding to alterations of SEC24 function is currently known only for SEC24D . Here, we reported that biallelic loss of SEC24C leads to a syndrome characterized by primary microcephaly, brain anomalies, epilepsy, hearing loss, liver dysfunction, anemia, and cataracts in an extended consanguineous family with 4 affected individuals. We showed that knockout of sec24C in zebrafish recapitulated important aspects of the human phenotype. SEC24C-deficient fibroblasts displayed alterations in the expression of several COPII components as well as impaired anterograde trafficking to the Golgi, indicating a severe impact on COPII function. Transcriptome analysis revealed that SEC24C deficiency also affected the proteasome and autophagy pathways. Moreover, a shift in the N-glycosylation pattern and deregulation of the N-glycosylation pathway suggested a possible secondary alteration of protein glycosylation, linking the described disorder with the congenital disorders of glycosylation.

Objectives: Neuronal ceroid lipofuscinosis type 11 (NCL11) is a rare disease that presents with progressive cognitive decline, epilepsy, visual impairment, retinal atrophy, cerebellar ataxia and cerebellar atrophy. We present herein a case of NCL11 in a patient diagnosed with neuromotor developmental delay, epilepsy, bronchiolitis obliterans and hypothyroidism. Case presentation: A 4-year-old male patient was admitted to our clinic with global developmental delay and a medical history that included recurrent hospitalizations for pneumonia at the age of 17 days, and in months 4, 5 and 7. Family history revealed a brother with similar clinical findings (recurrent pneumonia, hypothyroidism, hypotonicity, swallowing dysfunction and neuromotor delay) who died from pneumonia at the age of 22 months. Computed tomography of the thorax was consistent with bronchiolitis obliterans, while epileptic discharges were identified on electroencephalogram with a high incidence of bilateral fronto-centro-temporal and generalized spike-wave activity but no photoparoxysmal response. Cranial MRI revealed T2 hyperintense areas in the occipital periventricular white matter and volume loss in the white matter, a thin corpus callosum and vermis atrophy. A whole-exome sequencing molecular analysis revealed compound heterozygous c.430G>A (p.Asp144Asn) and c.415T>C (p.Cys139Arg) variants in the GRN gene. Conclusions: The presented case indicates that NCL11 should be taken into account in patients with epilepsy and neurodegenerative diseases.

Bi-allelic mutations in the wolframin gene (WFS1) cause Wolfram syndrome 1 (WS1 or DIDMOAD) characterized by non-autoimmune diabetes mellitus, optic atrophy, diabetes insipidus, sensorineural deafness, urinary tract abnormalities, and neuropsychiatric disorders. Patients presenting with an incomplete phenotype of WS1 were evaluated using homozygosity mapping and subsequent whole-exome sequencing. Four unrelated consanguineous Turkish families, including seven affected children, and their unaffected parents and siblings were evaluated. Homozygosity mapping was performed, followed by whole-exome sequencing of WFS1. Mutations were classified according to results of “in silico” analyses, protein prediction, and functional consequences. Homozygosity mapping confirmed shared homozygous regions on chromosome 4 (chr4p16.1) between the affected individuals, that was absent in their unaffected siblings. Exome sequencing identified three novel (c.1215T>A, c.554G>A, c.1525_1540dup) and one known (c.1522_1523delTA) mutations in WFS1. All mutations were predicted to cause stop codon leading to early termination of protein synthesis and complete loss-of-function. All patients were found to be homozygous for the change, with parents and other unaffected siblings being carriers. Our study expands the mutation spectrum of WSF1 mutations with three novel mutations. Homozygosity mapping may provide enrichment for molecular genetic analysis and early diagnosis of WS1 patients with incomplete phenotype, particularly in consanguineous pedigrees.