RESUMEN
Plectin is a cytoskeletal linker of intermediate filaments, encoded by the PLEC gene. Recently, plectin mutations have been identified in a pair of siblings with progressive familial intrahepatic cholestasis. Here, we reported two unrelated infants with plectinopathy causing cholestatic jaundice with novel variants in the PLEC gene. Trio exome sequencing identified compound heterozygous variants in the PLEC gene for each patient: c.71-11768C>T and c.4331G>T (p.Arg1444Leu) in Patient 1, and c.592C>T (p.Arg198Trp) and c.4322G>A (p.Arg1441His) in Patient 2. Immunofluorescence staining of liver samples from both patients revealed scattered signals of plectin in the cytoplasm of hepatocytes and reduced colocalization of plectin and cytokeratin 8. This study not only underscores the involvement of plectin in cholestasis but also highlights the utility of exome sequencing as a powerful diagnostic tool in identifying genetic underpinnings of infantile cholestasis.
RESUMEN
BACKGROUND: The signal transducer and activator of transcription 6 (STAT6) signaling pathway plays a central role in allergic inflammation. To date, however, there have been no descriptions of STAT6 gain-of-function variants leading to allergies in humans. OBJECTIVE: We report a STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with 3 affected members. METHODS: Exome sequencing and immunophenotyping of T-helper cell subsets were conducted. The function of the STAT6 protein was analyzed by Western blot, immunofluorescence, electrophoretic mobility shift assays, and luciferase assays. Gastric organoids obtained from the index patient were used to study downstream effector cytokines. RESULTS: We identified a heterozygous missense variant (c.1129G>A;p.Glu377Lys) in the DNA binding domain of STAT6 that was de novo in the index patient's father and was inherited by 2 of his 3 children. Severe atopic dermatitis and food allergy were key presentations. Clinical heterogeneity was observed among the affected individuals. Higher levels of peripheral blood TH2 lymphocytes were detected. The mutant STAT6 displayed a strong preference for nuclear localization, increased DNA binding affinity, and spontaneous transcriptional activity. Moreover, gastric organoids showed constitutive activation of STAT6 downstream signaling molecules. CONCLUSIONS: A germline STAT6 gain-of-function variant results in spontaneous activation of the STAT6 signaling pathway and is associated with an early-onset and severe allergic phenotype in humans. These observations enhance our knowledge of the molecular mechanisms underlying allergic diseases and will potentially contribute to novel therapeutic interventions.
Asunto(s)
Hipersensibilidad a los Alimentos , Mutación con Ganancia de Función , Niño , Humanos , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/metabolismo , Citocinas/metabolismo , ADNRESUMEN
A heterozygous nonsense variant in the TIGIT gene was identified in a patient in Thailand who had severe COVID-19, resulting in lower TIGIT expression in T cells. The patient's T cells produced higher levels of cytokines upon stimulation. This mutation causes less-controlled immune responses, which might contribute to COVID-19 severity.
Asunto(s)
COVID-19 , Receptores Inmunológicos , Humanos , COVID-19/genética , Citocinas/metabolismo , Receptores Inmunológicos/genética , SARS-CoV-2 , Tailandia/epidemiología , Codón sin SentidoRESUMEN
BACKGROUND: Inborn errors of immunity (IEI) comprise more than 400 rare diseases with potential life-threatening conditions. Clinical manifestations and genetic defects are heterogeneous and diverse among populations. Here, we aimed to characterize the clinical, immunologic, and genetic features of Thai pediatric patients with IEI. The use of whole-exome sequencing (WES) in diagnosis and clinical decision making was also assessed. METHODS: Thirty six unrelated patients with clinical and laboratory findings consistent with IEI were recruited from January 2010 to December 2020. WES was performed to identify the underlying genetic defects. RESULTS: The median age of disease onset was 4 months (range: 1 month to 13 years), and 24 were male (66.7%). Recurrent sinopulmonary tract infection was the most common clinical presentation followed by septicemia and severe pneumonia. Using WES, we successfully identified the underlying genetic defects in 18 patients (50%). Of the 20 variants identified, six have not been previously described (30%). According to the International Union of Immunological Societies (IUIS), 38.9% of these detected cases (7/18) were found to harbor variants associated with genes in combined immunodeficiencies with associated or syndromic features (Class II). CONCLUSION: The diagnostic yield of WES in this patient cohort was 50%. Six novel genetic variants in IEI genes were identified. The clinical usefulness of WES in IEI was demonstrated, emphasizing it as an effective diagnostic strategy in these genetically heterogeneous disorders.
Asunto(s)
Enfermedades de Inmunodeficiencia Primaria , Niño , Estudios de Cohortes , Genotipo , Humanos , Lactante , Masculino , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Tailandia , Secuenciación del ExomaRESUMEN
The use of rapid DNA sequencing technology in severely ill children in developed countries can accurately identify diagnoses and positively impact patient outcomes. This study sought to evaluate the outcome of Thai children and adults with unknown etiologies of critical illnesses with the deployment of rapid whole exome sequencing (rWES) in Thailand. We recruited 54 unrelated patients from 11 hospitals throughout Thailand. The median age was 3 months (range, 2 days-55 years) including 47 children and 7 adults with 52% males. The median time from obtaining blood samples to issuing the rWES report was 12 days (range, 5-27 days). A molecular diagnosis was established in 25 patients (46%), resulting in a change in clinical management for 24 patients (44%) resulting in improved clinical outcomes in 16 patients (30%). Four out of seven adult patients (57%) received the molecular diagnosis which led to a change in management. The 25 diagnoses comprised 23 different diseases. Of the 34 identified variants, 15 had never been previously reported. This study suggests that use of rWES as a first-tier investigation tool can provide tremendous benefits in critically ill patients with unknown etiology across age groups in Thailand.
Asunto(s)
Exoma/genética , Patología Molecular/métodos , Adolescente , Adulto , Niño , Preescolar , Enfermedad Crítica , Femenino , Pruebas Genéticas/métodos , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Tailandia , Secuenciación del Exoma/métodos , Adulto JovenRESUMEN
Cerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain, with localized flow being established by the polarized beating of the ependymal cell (EC) cilia. Here, we report a homozygous one base-pair deletion, c.1193delT (p.Leu398Glnfs*2), in the Kinesin Family Member 6 (KIF6) gene in a child displaying neurodevelopmental defects and intellectual disability. To test the pathogenicity of this novel human KIF6 mutation we engineered an analogous C-terminal truncating mutation in mouse. These mutant mice display severe, postnatal-onset hydrocephalus. We generated a Kif6-LacZ transgenic mouse strain and report expression specifically and uniquely within the ependymal cells (ECs) of the brain, without labeling other multiciliated mouse tissues. Analysis of Kif6 mutant mice with scanning electron microscopy (SEM) and immunofluorescence (IF) revealed specific defects in the formation of EC cilia, without obvious effect of cilia of other multiciliated tissues. Dilation of the ventricular system and defects in the formation of EC cilia were also observed in adult kif6 mutant zebrafish. Finally, we report Kif6-GFP localization at the axoneme and basal bodies of multi-ciliated cells (MCCs) of the mucociliary Xenopus epidermis. Overall, this work describes the first clinically-defined KIF6 homozygous null mutation in human and defines KIF6 as a conserved mediator of neurological development with a specific role for EC ciliogenesis in vertebrates.
Asunto(s)
Epéndimo/anomalías , Cinesinas/genética , Mutación , Trastornos del Neurodesarrollo/genética , Secuencia de Aminoácidos , Animales , Animales Modificados Genéticamente , Secuencia de Bases , Niño , Cilios/metabolismo , Cilios/patología , Consanguinidad , Epéndimo/metabolismo , Femenino , Expresión Génica , Homocigoto , Humanos , Hidrocefalia/genética , Discapacidad Intelectual/genética , Cinesinas/deficiencia , Cinesinas/metabolismo , Cinesinas/fisiología , Masculino , Ratones , Ratones Transgénicos , Modelos Animales , Trastornos del Neurodesarrollo/metabolismo , Trastornos del Neurodesarrollo/patología , Linaje , Eliminación de Secuencia , Distribución Tisular , Xenopus laevis , Pez CebraRESUMEN
OBJECTIVES: Glanzmann thrombasthenia (GT) is an autosomal recessive platelet disorder, caused by defects of the platelet integrin αIIbß3 (GPIIb/IIIa) resulting from pathogenic mutations in either ITGA2B or ITGB3. It is characterized by spontaneous mucocutaneous bleeding. The molecular features of GT in Thailand have not been identified. This study aimed to determine the clinical and molecular features of unrelated Thai patients with GT. METHODS: Four patients with clinically suspected GT were recruited at the Division of Pediatric Hematology/Oncology, King Chulalongkorn Memorial Hospital. The diagnosis was based on clinical and hematological parameters as well as genetic analysis. Whole exome sequencing (WES) was performed in all cases. RESULTS: Of the four patients studied, the median age at first suspicion of GT was 2.5 years. All presented with severe bleeding symptoms (WHO bleeding scale 3). Flow cytometry to assess the surface GPIIb/IIIa complex showed reduced expression. By WES, we successfully identified seven mutant alleles in ITGA2B. One alteration, the c.2915dup (p.Leu973Alafs*63), was detected in two unrelated families. One patient was homozygous for the c.617T>A (p.Val206Asp). Of the five different mutations, three have never been previously described. These include a missense, c.617T>A (p.Val206Asp), a deletion, c.1524_1533del (p.Gln508Hisfs*3), and a nonsense, c.2344C>T (p.Arg782Ter). CONCLUSION: This study reported three novel mutations expanding the genotypic spectrum of ITGA2B causing GT.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación , Trombastenia/diagnóstico , Trombastenia/genética , Alelos , Sustitución de Aminoácidos , Biomarcadores , Preescolar , Consanguinidad , Femenino , Genotipo , Humanos , Integrina alfa2/genética , Integrina beta3/genética , Masculino , Fenotipo , Secuenciación del ExomaRESUMEN
Disorders of sex development (DSD) can be classified as 46,XX DSD, 46,XY DSD, and sex chromosome DSD. Several underlying causes including associated genes have been reported. Steroidogenic factor-1 is encoded by the NR5A1 gene, a crucial regulator of steroidogenesis in the growth of the adrenal and gonadal tissues. It has been discovered to be responsible for 10 to 20% of 46, XY DSD cases. Here, we described a 2-month-old infant who had ambiguous genitalia and 46, XY. Using whole exome sequencing followed by polymerase chain reaction-Sanger sequencing, a novel heterozygous nonsense c.1249C > T (p.Gln417Ter) variant in the NR5A1 gene was identified. It is present in his mother but absent in his father and maternal aunt and uncle. At the age of 7 months, the patient received a monthly intramuscular injection of low-dose testosterone for 3 months in a row. His penile length and diameter increased from 1.8 to 3 cm and from 0.8 to 1.3 cm, respectively. The patient also had normal adrenal reserve function by adrenocorticotropic hormone stimulation test. This study identified a novel causative p.Q417X (c.1249C > T) variant in NR5A1 causing 46,XY DSD in a Thai boy which is inherited from his unaffected mother.
RESUMEN
AIMS: Analysis of the F8 gene helps predict the risk of developing factor VIII (FVIII) inhibitors and the depth of phenotype in haemophilia A (HA) patients. Since data in Southeast Asian countries remain scarce, we aim to study F8 variation correlated with HA phenotypes in Thailand. METHODS: Thai patients with HA were enrolled from seven haemophilia treatment centres during 2022-2023. Using peripheral blood DNA, inverse shifting-polymerase chain reaction (IS-PCR) for F8-intron 22 inversion (Inv22) and F8-intron 1 inversion (Inv1) was performed. Whole exome sequencing (WES) was explored in cases without Inv22/Inv1. RESULTS: Of 124 patients with HA, 91.9% were detected with a causative F8 variant, including Inv22 (30.6%), Inv1 (1.6%), missense (23.4%), nonsense (16.9%) and small insertion/deletion (16.1%) mutations. Inv22, small insertion/deletion and nonsense were associated with severe HA, compared with missense variants, by the ORs of 13.9 (95% CI, 4.2 to 56.7), 14.7 (95% CI, 3.4 to 104.7) and 15.6 (95% CI, 3.6 to 110.2), respectively. While nonsense variants affecting the light chain increased the risk of developing FVIII inhibitors (OR, 6.8; 95% CI, 1.5 to 32.6) compared with the low-risk (small insertion/deletion, missense and splice-site) variants. Twelve patients (9.7%) harboured novel F8 variants, comprising five missense (p.Pro540Leu, p.Ser564Pro, p.Leu668Pro, p.Ala1721Glu, p.His2024Pro), five small insertion/deletion (p.Val502SerfsTer13, p.Ile522PhefsTer13, p.Phe992LysfsTer11, p.Leu1223PhefsTer18, c.6427_6429+3delATGGTA) and one nonsense mutations (p.Glu1292Ter). CONCLUSIONS: IS-PCR followed by WES successfully assesses F8 alterations in most HA cases. With several unique variants, severe HA in Thailand is considerably caused by Inv22, small insertion/deletion and nonsense, whereas missense variants are more responsible for nonsevere HA phenotypes.
RESUMEN
Summary Non-syndromic oral clefts comprising cleft lip with and without cleft palate (CL/P) and cleft palate only (CPO) are common birth defects worldwide. Their aetiology involves both environmental and genetic factors. FOXE1 has previously been reported to be associated with oral clefts in some populations. Here, we investigate whether mutations in FOXE1 play a part in the formation of oral cleft in a Thai population. We first performed PCR-RFLP to genotype a previously reported associated polymorphism, c.-1204C > G (rs111846096), in our cohort. No association was found. In addition, two unrelated unaffected controls were found to be homozygous GG, indicating that homozygous GG at this c.-1204 position was not sufficient for the development of oral clefts. We then sequenced the entire coding region of FOXE1 in 458 unrelated individuals (146 CPOs, 108 CL/Ps and 204 Thai controls). Five different non-synonymous variants, c.274G > T (p.D92Y), c.569C > G (p.P190R), c.569C > T (p.P190L), c.664C > T (p.R222C) and c.1090G > A (p.G364S), were identified in CPOs and one, c.572C > G (p.P191R), in CL/P. All these six variants were in heterozygous state, each identified in one patient, and absent in 204 controls. Except the p.P190R, which was previously reported, the other five variants were novel. Our study identifies probable susceptibility variants of FOXE1 for oral clefts in the Thai population.
Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Factores de Transcripción Forkhead/genética , Predisposición Genética a la Enfermedad , Mutación , Secuencia de Bases , Cartilla de ADN , Humanos , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , TailandiaRESUMEN
The spectra of underlying genetic variants for various clinical entities including focal segmental glomerulosclerosis (FSGS) vary among different populations. Here we described the clinical and genetic characteristics of biopsy-proven FSGS patients in Thailand. Patients with FSGS pathology, without secondary causes, were included in our study. Clinical laboratory and pathological data were collected. Whole-exome sequencing (WES) was subsequently performed. 53 unrelated FSGS patients were recruited. 35 patients were adults (66.0%), and 51 patients were sporadic cases (96.2%). Clinical diagnosis before kidney biopsy was steroid-resistant nephrotic syndrome (SRNS) in 58.5%, and proteinuric chronic kidney disease in 32.1%. Using WES, disease-associated pathogenic/likely pathogenic (P/LP) variants could be identified in six patients including the two familial cases, making the P/LP detection rate of 11.3% (6/53). Of these six patients, two patients harbored novel variants with one in the COL4A4 gene and one in the MAFB gene. Four other patients carried previously reported variants in the CLCN5, LMX1B, and COL4A4 genes. Four of these patients (4/6) received immunosuppressive medications as a treatment for primary FSGS before genetic diagnosis. All four did not respond to the medications, emphasizing the importance of genetic testing to avoid unnecessary treatment. Notably, the mutation detection rates in adult and pediatric patients were almost identical, at 11.4% and 11.1%, respectively. In conclusion, the overall P/LP variant detection rate by WES in biopsy-proven FSGS patients was 11.3%. The most identified variants were in COL4A4. In addition, three novel variants associated with FSGS were detected.
Asunto(s)
Glomeruloesclerosis Focal y Segmentaria , Síndrome Nefrótico , Adulto , Humanos , Niño , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Secuenciación del Exoma , Pueblos del Sudeste Asiático , Tailandia , Mutación , Síndrome Nefrótico/genética , BiopsiaRESUMEN
Pharmacoresistant epilepsy presenting during infancy poses both diagnostic and therapeutic challenges. We aim to identify diagnostic yield and treatment implications of exome sequencing (ES) as first-tier genetic testing for infantile-onset pharmacoresistant epilepsy. From June 2016 to December 2020, we enrolled patients with infantile-onset (age ≤ 12 months) pharmacoresistant epilepsy. 103 unrelated patients underwent ES. Clinical characteristics and changes in management due to the molecular diagnosis were studied. 42% (43/103) had epilepsy onset within the first month of life. After ES as first-tier genetic testing, 62% (64/103) of the cases were solved. Two partially solved cases (2%; 2/103) with heterozygous variants identified in ALDH7A1 known to cause autosomal recessive pyridoxine dependent epilepsy underwent genome sequencing (GS). Two novel large deletions in ALDH7A1 were detected in both cases. ES identified 66 pathogenic and likely pathogenic single nucleotide variants (SNVs) in 27 genes. 19 variants have not been previously reported. GS identified two additional copy number variations (CNVs). The most common disease-causing genes are SCN1A (13%; 13/103) and KCNQ2 (8%; 8/103). Eight percent (8/103) of the patients had treatable disorders and specific treatments were provided resulting in seizure freedom. Pyridoxine dependent epilepsy was the most common treatable epilepsy (6%; 6/103). Furthermore, 35% (36/103) had genetic defects which guided gene-specific treatments. Altogether, the diagnostic yield is 64%. Molecular diagnoses change management in 43% of the cases. This study substantiates the use of next generation sequencing (NGS) as the first-tier genetic investigation in infantile-onset pharmacoresistant epilepsy.
Asunto(s)
Variaciones en el Número de Copia de ADN , Epilepsia , Humanos , Lactante , Secuenciación del Exoma , Piridoxina , Pruebas Genéticas/métodos , Epilepsia/genéticaRESUMEN
AIMS: Von Willebrand disease (VWD) is an inherited haemostatic disorder with a wide range of bleeding phenotypes based on von Willebrand factor (VWF) levels. Multiple assays including VWF gene analysis are employed to correctly diagnose VWD and its subtypes. However, data on VWF mutations among Southeast Asian populations are lacking. We, therefore, aimed to explore genetic variations in Thai patients with type 2 and type 3 VWD by whole exome sequencing (WES). METHODS: In this multicentre study, Thai patients with type 2 and type 3 VWD, according to the definitions and VWF levels recommended by the international guidelines, were recruited. WES was performed using DNA extracted from peripheral blood in all cases. The novel variants were verified by Sanger sequencing. RESULTS: Fifteen patients (73% females; median age at diagnosis 3.0 years) with type 2 (n=12) and type 3 VWD (n=3) from 14 families were enrolled. All patients harboured at least one VWF variant. Six missense (p.Arg1374Cys, p.Arg1374His, p.Arg1399Cys, p.Arg1597Trp, p.Ser1613Pro, p.Pro1648Arg) and one splice-site (c.3379+1G>A) variants in the VWF gene were formerly described. Notably, six VWF variants, including three missense (p.Met814Ile, p.Trp856Cys, p.Pro2032Leu), one deletion (c.2251delG) and two splice-site (c.7729+4A>C, c.8115+2delT) mutations were novelly identified. Compound heterozygosity contributed to type 2 and type 3 VWD phenotypes in two and one patients, respectively. CONCLUSIONS: Type 2 and type 3 VWD in Thailand demonstrate the mutational variations among VWF exons/introns with several unique variants. The WES-based approach potentially provides helpful information to verify VWD diagnosis and facilitate genetic counselling in clinical practice.
RESUMEN
MRPS23 is a nuclear gene encoding a mitochondrial ribosomal protein. A patient with a mitochondrial disorder was found to carry a variant in MRPS23. More cases are necessary to establish MRPS23 as a mitochondrial disease gene. Of 5134 exomes performed in our center, we identified five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23. Detailed clinical findings, mitochondrial enzyme activity assays from cultured skin fibroblasts, PCR-Sanger-sequencing, and variant age estimation were performed. Their available family members were also studied. Eight members homozygous for the MRPS23 p.P40L were identified. All were from Hmong hilltribe. Seven presented with alteration of consciousness and recurrent vomiting, while the eighth who was a younger brother of a proband was found pre-symptomatically. Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV. PCR-Sanger-sequencing confirmed the variant, which was estimated to have occurred 1550 years ago. These results establish the MRPS23-associated mitochondrial disorder inherited in an autosomal recessive pattern and provide insight into its clinical and metabolic features.
Asunto(s)
Acidosis Láctica , Enfermedades Mitocondriales , Masculino , Humanos , Enfermedades Mitocondriales/genética , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas Ribosómicas/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Acidosis Láctica/genéticaRESUMEN
AIMS: Congenital neutropaenia is a rare inherited disorder that mainly affects neutrophils causing severe infection. Mutations in several genes have been implicated in the disease pathogenesis. The genetic defects may vary in different populations, influenced by ethnicity and geographical location. Here we describe the clinical and genotypic characteristics of seven unrelated Thai cases with congenital neutropaenia. METHODS: Seven unrelated patients with congenital neutropaenia were enrolled (5 female and 2 male) at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Clinical and laboratory data were collected. Whole exome sequencing (WES) analysis was performed in all cases. RESULTS: WES successfully identified disease-causing mutations in the ELANE gene in all cases, including two novel ones: a heterozygous 12 base pair (bp) inframe insertion (c.289_300dupCAGGTGTTCGCC; p.Q97_A100dup) and a heterozygous 18 bp inframe deletion (c.698_715delCCCCGGTGGCACAGTTTG; p.A233_F238delAPVAQF). Five other previously described ELANE mutations (p.Arg103Pro, p.Gly214Arg, p.Trp241X, p.Ser126Leu and p.Leu47Arg) were also detected. CONCLUSIONS: All Thai patients with congenital neutropaenia in this study harboured causative mutations in the ELANE gene, suggesting it the most common associated with the disease. Two novel mutations were also identified, expanding the genotypic spectrum of ELANE.
Asunto(s)
Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Elastasa de Leucocito/genética , Mutación , Neutropenia/congénito , Niño , Preescolar , Síndromes Congénitos de Insuficiencia de la Médula Ósea/diagnóstico , Síndromes Congénitos de Insuficiencia de la Médula Ósea/tratamiento farmacológico , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Lactante , Masculino , Neutropenia/diagnóstico , Neutropenia/tratamiento farmacológico , Neutropenia/genética , Fenotipo , Tailandia , Resultado del Tratamiento , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 vaccination reduces morbidity and mortality associated with coronavirus disease 2019 (COVID-19); unfortunately, it is associated with serious adverse events, including sudden unexplained death (SUD). OBJECTIVE: We aimed to study the genetic basis of SUD after COVID-19 vaccination in Thailand. METHODS: From April to December 2021, cases with natural but unexplained death within 7 days of COVID-19 vaccination were enrolled for whole exome sequencing. RESULTS: Thirteen were recruited, aged between 23 and 72 years; 10 (77%) were men, 12 were Thai; and 1 was Australian. Eight (61%) died after receiving the first dose of vaccine, and 7 (54%) died after receiving ChAdOx1 nCoV-19; however, there were no significant correlations between SUD and either the number or the type of vaccine. Fever was self-reported in 3 cases. Ten (77%) and 11 (85%) died within 24 hours and 3 days of vaccination, respectively. Whole exome sequencing analysis revealed that 5 cases harbored SCN5A variants that had previously been identified in patients with Brugada syndrome, giving an SCN5A variant frequency of 38% (5 of 13). This is a significantly higher rate than that observed in Thai SUD cases occurring 8-30 days after COVID-19 vaccination during the same period (10% [1 of 10]), in a Thai SUD cohort studied before the COVID-19 pandemic (12% [3 of 25]), and in our in-house exome database (12% [386 of 3231]). CONCLUSION: These findings suggest that SCN5A variants may be associated with SUD within 7 days of COVID-19 vaccination, regardless of vaccine type, number of vaccine dose, and presence of underlying diseases or postvaccine fever.
Asunto(s)
COVID-19 , Masculino , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Femenino , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , ChAdOx1 nCoV-19 , Tailandia/epidemiología , Pandemias , Australia , Muerte Súbita/epidemiología , Muerte Súbita/etiología , Vacunación/efectos adversosRESUMEN
Catechol-O-methyltransferase (genetic locus, COMT) is a major enzyme involved in catecholamine metabolism and has been associated with numerous psychiatric phenotypes. We studied COMT SNPs and haplotypes in cocaine-induced paranoia (CIP) in African-American (AA) and European-American (EA) populations. We genotyped 17 SNPs across the COMT locus in 319 AA pedigrees (848 individuals) and 302 EA pedigrees (707 individuals). Family-controlled association analyses were conducted using FBAT. We found SNP rs737865 to be nominally significantly associated in the AA family population (P = 0.05). In EAs, the best-known marker, rs4680 (Val158Met), was nominally significant in additive models (P = 0.03). SNP rs174696 also showed nominal significance in additive models (P = 0.02). We considered the three SNPs (rs737866-rs4680-rs174696) together in haplotype analysis in both family populations, using HBAT. The A-A-T haplotype was significantly associated with CIP in EAs (Z = 2.845; P = 0.0044, global P = 0.020). We then studied COMT SNPs in an additional 738 AA and 404 EA unrelated cocaine dependent individuals with and without paranoia. The A-A-T haplotype was significantly associated to CIP in the AA unrelated population (P = 0.0015). Two haplotypes, A-G-C and A-A-C, were significant in the EA unrelated population (P = 0.001 and 0.0003). We also identified rs4680 and three other SNPs, rs933271, rs5993883, and rs740603, as potentially functional variants, as predicted by a signature of positive selection in unrelated EAs and AAs. Based on our robust family-controlled and unrelated-affected analyses, we conclude that COMT is associated with CIP, possibly as a result of its role in the metabolism of dopamine and norepinephrine.
Asunto(s)
Negro o Afroamericano/genética , Catecol O-Metiltransferasa/genética , Trastornos Relacionados con Cocaína/genética , Trastornos Paranoides/inducido químicamente , Trastornos Paranoides/genética , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Estudios de Casos y Controles , Cocaína/farmacología , Dopamina/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Norepinefrina/metabolismoRESUMEN
BACKGROUND: In approximately half of patients with epilepsy and intellectual disability (ID), the cause is unidentified and could be a mutation in a new disease gene. PATIENT DESCRIPTION: To determine the discovery of disease-causing mutation in a female patient with epilepsy and ID, we performed trio whole-exome sequencing, reverse transcription polymerase chain reaction (RT-PCR) followed by Sanger sequencing. RESULTS: Trio whole-exome sequencing was performed and revealed a novel de novo heterozygous stop-loss c.467A > T (p.*156Leuext*35) mutation in the ATP6V0C gene. Using RNA from leukocytes, RT-PCR followed by Sanger sequencing showed the existence of the mutant RNA, and real-time PCR demonstrated that the patient's ATP6V0C RNA level was approximately half of that in her parents, suggesting haploinsufficiency as a pathomechanism. CONCLUSION: These findings, along with previous reports of individuals with similar phenotypes and variants in the same gene, substantiate ATP6V0C as a gene causing epilepsy with ID.
Asunto(s)
Epilepsia/genética , Discapacidad Intelectual/genética , ATPasas de Translocación de Protón Vacuolares/genética , Femenino , Humanos , MutaciónRESUMEN
Hereditary thrombocytopenia comprises extremely diverse diseases that are difficult to diagnose by phenotypes alone. Definite diagnoses are helpful for patient (Pt) management.To evaluate the role of whole exome sequencing (WES) in these Pts.Cases with unexplained long-standing thrombocytopenia and/or suggestive features were enrolled to the observational study. Bleeding scores and blood smear were evaluated. The variant pathogenicity from WES was determined by bioinformatics combined with all other information including platelet aggregometry, flow cytometry, and electron microscopy (EM).Seven unrelated Pts were recruited. All were female with macrothrombocytopenia. Clinical bleeding was presented in four Pts; extra-hematological features were minimal and family history was negative in every Pt. WES successfully identified all the 11 responsible mutant alleles; of these, four have never been previously reported. Pt 1 with GNE-related thrombocytopenia showed reduced lectin binding by flow cytometry, increased glycogen granules by EM and a novel homozygous mutation in GNE. Pts 2 and 3 had phenotypic diagnoses of Bernard Soulier syndrome and novel homozygous mutations in GP1BB and GP1BA, respectively. Pt 4 had impaired microtubule structures, concomitant delta storage pool disease by EM and a novel heterozygous TUBB1 mutation. Pt 5 had sitosterolemia showing platelets with reduced ristocetin responses and a dilated membrane system on EM with compound heterozygous ABCG5 mutations. Pts 6 and 7 had MYH9 disorders with heterozygous mutations in MYH9.This study substantiates the benefits of WES in identifying underlying mutations of macrothrombocytopenia, expands mutational spectra of four genes, and provides detailed clinical features for further phenotype-genotype correlations.
Asunto(s)
Secuenciación del Exoma , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Adolescente , Adulto , Estudios Transversales , Femenino , Humanos , Persona de Mediana Edad , Mutación , Adulto JovenRESUMEN
PURPOSE: To evaluate the association of single nucleotide polymorphisms (SNPs) and the intronic expansion of a trinucleotide repeat (TNR) in the TCF4 gene with Fuchs endothelial corneal dystrophy (FECD) in a Thai population. METHODS: In total, 54 Thai FECD patients and 54 controls were recruited for the study. Five SNPs (rs613872, rs2123392, rs17089887, rs1452787, and rs1348047), previously reported to be associated with FECD, were genotyped by direct sequencing. The repeat length was determined by direct sequencing of PCR-amplified DNA (a short tandem repeat; STR assay) and by triplet repeat primed PCR (TP-PCR). RESULTS: Only one of the 54 patients with FECD harboured rs613872 (1.9%). Four SNPs (rs2123392, rs17089887, rs1452787, and rs1348047), which are not rare polymorphisms in the Thai population, were found in approximately half of the patients. Of the 54 patients, 21 (1 homozygous and 20 heterozygous patients; 39%) harboured a TNR ≥ 40, while 33 patients (61%) harboured a TNR < 40. CONCLUSIONS: The association of TNR expansion in TCF4 with FECD is shown for the first time in the Thai population. The intronic TNR expansion identified in various ethnic groups underlines the importance of expansion as a potent pathophysiological cause of FECD.