The association between VSX1 exon3 gene variants and keratoconus in Malaysian patients

Purpose: This case-control study aims to examine possible associations of VSX1 exon3 gene variants with the development of keratoconus (KC) in Malaysian patients. Methods: A case-control study was done on 42 keratoconus cases, 127 family member controls, and 96 normal controls. Results: Three gene variants, p.A182A, p.P237P, and p.R217H showed significant associations with keratoconus (P < 0.05). While p.A182A and p.P227P were more prevalent than in the family and normal controls (OR 3.14–4.05), the reverse was observed with p.R217H (OR 0.086–1.59). With Haploview analysis, p.A182A and p.P237P were shown to be in linkage disequilibrium (LD) (LOD (logarithm of the odds score) score of 2.0, r2 of 0.957, and 95% confidence interval (CI) of 0.96–1.00). Conclusion: The study results suggest that the p.A182A and p.P237P variants could have contributed to the development of keratoconus in some Malaysians and that these two variants are likely to be co?inherited. In contrast, the p.R217H variant appeared to confer some protection against the development of keratoconus.

Clinical and genetic study of developmental and epileptic encephalopathy in argentinean pediatric patients / Estudio clínico y genético de encefalopatía epiléptica y del desarrollo en pacientes pediátricos argentinos

Abstract Introduction: The aim of this study was to extend our knowledge of the genetic background of Argentinean pediatric patients with developmental and epileptic encephalopathy (DEE) applying a next generation sequencing (NGS) panel. Methods: Thirty one patients with DEE were studied, including these phenotypes: Dravet syndrome (n:7), Dravet like syndrome (n:3), West syndrome (WS) (n:6), WS that evolved to Lennox-Gastaut syndrome (LGS) (n:4), epilepsy of infancy with migrating focal seizures (n:2), continuous spikes and waves during slow sleep evolving to LGS (n:1), LGS (n:1), myoclonic status in non-progressive encephalopathy (n:1), myoclonic atonic epilepsy (n:1), epileptic encephalopathy with multifocal spikes (n:1) and unclassified epileptic encephalopathy (n:4). Fifty-two genes frequently associated with DEE were studied by NGS in genomic DNA from peripheral blood. Results: Relevant variants were detected in 12 cases; 6 novel pathogenic or likely pathogenic variants, 6 previously reported as pathogenic and 1 variant of unknown sig nificance. Single-nucleotide heterozygous variants were identified in the SCN1A (5), GABRG2 (1), STXBP1 (2) genes, a mosaic variant in SCN2A (1) and a homozygous variant in SCN1B (1). Additionally, a heterozygous deletion involving the SCN1A, SCN2A and SCN3A genes (1), and the most frequent triplet repeat expansion in the ARX gene (1) were detected. Discussion: Genetic diagnosis was made in 39% of patients. We emphasize the importance of considering mosaic variants, copy number variants and hereditary forms when designing and interpreting molecular studies, to optimize diagnosis and management of patients. Approximately 42% of the de tected variants were novel, expanding the knowledge of the molecular basis of DEEs in Latin-American patients.

Resumen Introducción: El objetivo del estudio fue ampliar el conocimiento de las bases moleculares de las encefalopatías epilépticas y del desarrollo (EED) en pacientes pediátricos argentinos aplicando un panel de secuenciación de nueva generación (NGS). Métodos: Se analizaron 31 pacientes con los fenotipos clínicos de síndrome de Dra vet (n:7), síndrome símil Dravet (n:3), síndrome de West (SW) (n:6), SW que evoluciona a síndrome de Lennox Gastaut (SLG)(N:4), epilepsia de la infancia con crisis focales migratorias (n:2), actividad de punta onda continua durante el sueño que evolucionan a SLG (n:1), SLG (n:1), encefalopatía no progresiva con estatus mioclónico (n:1), epilepsia mioclónica atónica (n:1), encefalopatía epiléptica con espigas multifocales (n:1) y encefalopatía epiléptica indeterminada (n:4). Se estudiaron los 52 genes más frecuentemente asociados a EED a través de NGS, en ADN extraído de sangre periférica. Resultados: Se identificaron variantes relevantes en 12 casos, de las cuales 5 fueron nuevas y 6 previamente reportadas como patogénicas o posiblemente patogénicas, mien tras que una variante fue clasificada como de significado incierto. Variantes heterocigotas, de nucleótido único, se identificaron en los genes SCN1A (5), GABRG2 (1), STXBP1 (2), una variante en mosaico en SCN2A (1) y otra homocigota en SCN1B (1). Además, se detectó una deleción que involucra a los genes SCN1A, SCN2A y SCN3A (1) y la expansión de repeticiones de tripletes más frecuente en el gen ARX (1). Discusión: Se alcanzó el diagnóstico molecular en el 39% de los pacientes. Remarcamos la importancia de considerar variantes en mosaico, variantes en el número de copias y formas heredadas al momento de diseñar e interpretar los estudios moleculares, de tal forma de optimizar el diagnóstico y seguimiento de los pacientes con EED. Cabe destacar, que el 42% de las variantes detectadas fueron nuevas, ampliando nuestro conocimiento sobre las bases mole culares de las EED en población latino americana.

Association between the CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants with vitiligo: study on a Mexican population

Abstract Background: Vitiligo is characterized by an autoimmune response targeting melanocytes, thus resulting in skin depigmentation. There are several genetic components involved in the development of vitiligo, of which various gene polymorphisms are currently considered as risk factors. For example, the CTLA4 (T-lymphocyte antigen 4) +49A/G (rs231775) and CT60 (rs3087243) gene variants have been associated with a predisposition for autoimmune diseases in different populations; however, their involvement in the development of vitiligo remains controversial. Objective: We evaluated the association between vitiligo and the CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants in a Mexican population. Methods: A total of 116 vitiligo patients and 117 control subjects from northeast Mexico were included in the study and analyzed through PCR-RFLP to determine whether there is an association between vitiligo and CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants. Results: No statistical difference was observed for both gene polymorphisms between vitiligo patients and controls (p > 0.05). Otherwise, vitiligo activity, family history of vitiligo, personal history of autoimmune diseases, or sex did not show any difference (p > 0.05). Conclusion: As suggested by the analysis of a northeastern Mexican population, the CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants do not constitute a risk factor in the development of vitiligo.

Phenotype and genotype features of 11 children with dystonia 28 caused by KMT2B variants / 中华实用儿科临床杂志

Objective:To summarize the clinical characteristics of children with dystonia 28 (DYT28) caused by KMT2B gene variations so as to improve clinicians′ understanding of the disease. Methods:The clinical manifestations, treatment and gene variation data of 11 children with DYT28 caused by KMT2B gene variations were retrospectively collected and analyzed.The subjects were recruited from the Department of Neurology, Beijing Children′s Hospital, Capital Medical University from March 2018 to January 2021.The patients were followed up. Results:There were 8 males and 3 females.The age at onset was ranging from 1 month to 6 years without inducement.Eight cases were gene-ralized dystonia and 3 cases were multifocal dystonia.The initial symptoms of 7 cases were unilateral or bilateral lower limbs tiptoeing.Four cases presented dysarthria, retching or swallowing difficulties at onset.As the disease progressed, all the cases had laryngeal dystonia, 10 cases had lower limbs dystonia, and 8 cases had upper limbs dystonia.Six cases were complicated with other dyskinesia symptoms.Ten cases had varying degrees of short stature, microcephalus, micrognathia, musculoskeletal abnormalities, intellectual disability, endocrinopathies and sleep difficulties.The brain magnetic resonance imaging showed abnormal in only 1 case.Eleven KMT2B gene pathogenic variants were found, including 8 frameshift variants, 1 in-frame variant and 2 missense variants.Four variants were novel.Eleven cases were followed up at the age of 1 year and 7 months to 17 years and 9 months.One case wasn′t given therapy.The dystonia in 3 cases was mildly improved after medication.Dysfunction of urination and defecation was disappeared in 1 case after medication.The symptom of 6 cases had no improvement after drug therapy.Among the above 6 cases, 5 drug refractory cases had deep brain stimulation, and their dystonia symptoms are all obviously improved; 2 cases had normal control of urination and defecation after deep brain stimulation.The motor scores in the Burke-Fahn-Marsden dystonia rating scale were improved by 55.8%-90.7%, and the disability scores were improved by 14.8%-69.6%. Conclusions:DYT28 caused by KMT2B gene variations is one of the most common and early-onset genetic dystonia in children.The dystonia symptom progresses from local parts to the whole body, prominently involving laryngeal muscles and lower limbs.Control of urination and defecation requires attention.Patients with mild dystonia symptoms can be effectively treated by drugs.However, patients with severe dystonia symptoms were drug refractory, and their dystonia symptoms can be effectively improved by deep brain stimulation.

Genes frequently associated with sudden death in primary hypertrophic cardiomyopathy / Genes frecuentemente asociados con muerte súbita en miocardiopatía hipertrófica primaria

Abstract Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy without apparent cardiac justification. Sudden cardiac death may be the first manifestation of the disease. It occurs mainly in adulthood and can be seen in childhood and adolescence where genetic origin predominates. Primary HCM (“familial”) is inherited in an autosomal dominant pattern in the 25 subtypes informed in Online Mendelian Inheritance in Man. The proteins encoded by the mutated genes are part of the sarcomere in the cardiac cells, being the thick filament the most frequently affected, with the worst prognosis. In the present article, we describe the Mendelian inheritance of the disease and the two most associated genes with sudden death: MYBPC3 and MYH7.

Resumen La miocardiopatía hipertrófica (MCH) es el aumento de grosor de la pared ventricular izquierda no relacionada con otras alteraciones cardíacas. Es una enfermedad que puede presentar como primera manifestación clínica la muerte súbita y de ahí su relevancia clínica. Aunque se presenta sobre todo en la edad adulta, puede aparecer durante la infancia y adolescencia, en las que predominan los casos de origen hereditario. La MCH primaria, de causa genética, muestra en particular un patrón de herencia autosómico dominante en los 25 subtipos reconocidos en OMIM (Online Mendelian Inheritance in Man). Las proteínas codificadas por los genes mutantes forman parte del sarcómero en células musculares cardíacas, y las variantes patogénicas de filamentos gruesos son las de mayor frecuencia y peor pronóstico. En este artículo se describen la herencia mendeliana de la enfermedad y la relación con muerte súbita de los genes más frecuentemente encontrados en ella: MYBPC3 y MYH7.

Association Of Eda Gene Polymorphisms Rs 372024, Rs 3764746, Rs 3795170 In Skeletal Class I Cases With Dental Crowding

The EDA gene, associated with X linked hydrotic form of Ectodermal Dysplasia, its mutations could potentially lead to differential gene expression that causes large tooth phenotype, which has been suggested to cause dental crowding. We analyzed the association of genetic polymorphisms in EDA gene variants rs 372024, rs 3764746, and rs 3795170 among Skeletal Class I crowding cases using blood samples of 30 cases and 30 controls, which were subjected to PCR amplication and DNA sequencing. Based on the statistical analysis using the Z test we found CG and GG genotype for rs3764746 and GT and TT genotype for rs3795170 showed a statistically signicant result. These results suggest that EDA gene variants rs3764746 and rs3795170 could be genetic markers for dental crowding in our population while EDA gene variant rs372024 did not show any signicant association in our population. These ndings can provide in-depth knowledge, regarding the genetic inuences on the incidence of crowding of teeth.

Diagnostic challenges posed by a rare alpha globin chain variant Hb Fontainebleau in a pregnant female and its potential effects in her children in view of multiple globin gene defects in her husband

Alpha globin chain variants per se do not cause severe morbidity and mortality but can modify – usually ameliorate – the clinical manifestations of beta globin chain variants when co-inherited with the latter. They also pose challenges in interpretation of high-performance liquid chromatography histograms and require molecular analysis for proper characterization. Hemoglobin (Hb) Fontainebleau is a rare alpha globin chain variant [alpha 21(B2) Ala?Pro], of which only three families have been reported from India in the past. Here, we describe a case of Hb fontainebleau detected in heterozygous condition in a 19-year-old primigravida. Her husband was found to have a double heterozygous state for HbQ India and beta-thalassemia trait. This opens up the possibility of multiple combinations of hemoglobinopathies in the offspring.

Correlation between polymorphisms of surfactant protein A1 rs1059047 and rs1136450 and respiratory distress syndrome in Mongolian premature infants / 中华急诊医学杂志

Objective To study the correlation between polymorphisms of surfactant protein A1 rs1059047 and rs1136450 and respiratory distress syndrome (RDS) in Mongolian premature infants in Inner Mongolia.Methods Totally 50 Mongolian RDS premature infants in our ward were recruited as the case group (33 males and 17 females),and another 50 Mongolian non-RDS premature infants with same ethnicity,same sex and gestational age were served as the control group (29 males and 21 females).Single nucleotide polymorphisms of SP-A1 rs1059047 and,rs1136450 and allele haploids (6A,6A2,and 6A3) were detected by polymerase chain reaction-single strand conformation polymorphism gene detection technology and were compared between the case and control groups.Results Threegenotypes,CC,TT,CT were detected in the case and control groups at rs1059047,all ofwhich were mainly TT genotype.There was no significant difference in genotype frequency between the two groups (x2=1.429,P ＞ 0.05).Two genotypes,CG and GG,were detected in the case and control groups at rsl 136450,and CG was the dominant genotype.There was no significant difference in genotype frequency between the two groups (x2=1.624,P＞0.05).The distribution frequency of SP-A1 allele haploids (6A,6A2,6A3) in the case group was 36％,68％ and 42％,respectively,and 62％,46％ and 50％ in the control group,respectively.There was no significant differencein the frequency of allele haploid 6A3 between the two groups (x2=0.502,P＞0.05);but there was a significantly difference in the frequency of allele haploids (6A,6A2) between the two groups (x2=6.763,4.937,P＜0.05).Conclusions The alleles and allele fiequency of SP-A1 (rs1059047,rs1136450) were not associated with RDS in Mongolian premature infants.However,SP-A1 allele haploid 6A2 is the susceptible gene for RDS in Mongolian premature infants,and haploid 6A is the protective gene.

Genetic predisposition in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has reached global epidemic proportions. Although the disease is relatively benign in the early stages, when severe clinical forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma, occur, they result in worsening the long-term prognosis. A growing body of evidence indicates that NAFLD develops from a complex process in which many factors, including genetic susceptibility and environmental insults, are involved. In this review, we focused on the genetic component of NAFLD, with special emphasis on the role of genetics in the disease pathogenesis and natural history. Insights into the topic of the genetic susceptibility in lean individuals with NAFLD and the potential use of genetic tests in identifying individuals at risk are also discussed.

Detection of Cytomegalovirus Infection and IE Gene Variants in Renal Transplant Recipients by Shell Vial Culture and DNA Methods / 대한신장학회잡지

Cytomegalovirus (CMV) is a ubiquitous virus and its infections occur commonly after renal transplantation and immunosuppressive therapy. Early and accurate laboratory diagnosis of CMV infection in renal transplant is necessary but often difficult. To find optimal diagnostic methods for CMV infection, we compared shell vial culture and polymerase chain reaction (PCR) and Southern blot of PCR products. A total of 301 specimens of urine, blood neutrophils, tissues, or body fluids were obtained from 75 renal transplant recipients and were submitted to shell vial culture for CMV as well as DNA PCR using primers for immediate early(IE) gene of CMV. The human fibroblast cell line (MRC-5) was used to culture CMV and were examined with immunofluorescence staining using monoclonal antibody to the early antigen of CMV. The PCR products (274 and 379 bp) were detected by gel electrophoresis and ethidium bromide staining. When PCR products were not clearly visible on electrophoresis, PCR products were analyzed by Southern blot using IE gene probe. Sixty four(85.3%) of 75 renal transplant recipients showed CMV infection as analyzed by PCR and Southern blot as well as shell vial culture. On shell vial culture, CMV were detected in 81 specimens from 30(40%) renal transplant recipients in viremic state. On PCR and Southern blot analysis CMV were detected in 55 and 26 specimens, respectively from 59 patients. The sensitivity of culture and PCR to detect CMV infection were 42.4% and 83.3%, respectively. The results of two studies were concordant in 48%. PCR and Southern blot did not detect CMV in 10 and 5 culture proven CMV positive samples, respectively. Mutant CMV were found in 3 patients which showed 5-10 bp deletion in IE gene. Moreover, DNA sequencing analysis showed 5 mutant strains among 11 strains which appeared same by PCR prodcut. These results suggest that PCR followed by Southern blot may be more sensitive, but less specific than shell vial culture in the diagnosis of CMV disease. PCR followed by Southern blot may not detect mutant CMV. Combined analysis using both shell vial culture and PCR followed by Southern blot may be necessary to diagnose CMV infection in renal transplant recipients.