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1.
Epilepsy Behav ; 145: 109266, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37385119

RESUMEN

Zellweger spectrum disorders (ZSD) are rare autosomal recessive disorders caused by defects in peroxisome biogenesis factor (PEX; peroxin) genes leading to impaired transport of peroxisomal proteins with peroxisomal targeting signals (PTS). Four patients, including a pair of homozygotic twins, diagnosed as ZSD by genetic study with different clinical presentations and outcomes as well as various novel mutations are described here. A total of 3 novel mutations, including a nonsense, a frameshift, and a splicing mutation, in PEX1 from ZSD patients were identified and unequivocally confirmed that the p.Ile989Thr mutant PEX1 exhibited temperature-sensitive characteristics and is associated with milder ZSD. The nature of the p.Ile989Thr mutant exhibited different characteristics from that of the other previously identified temperature-sensitive p.Gly843Asp PEX1 mutant. Transcriptome profiles under nonpermissive vs. permissive conditions were explored to facilitate the understanding of p.Ile989Thr mutant PEX1. Further investigation of molecular mechanisms may help to clarify potential genetic causes that could modify the clinical presentation of ZSD.


Asunto(s)
Síndrome de Zellweger , Humanos , Niño , Síndrome de Zellweger/genética , Síndrome de Zellweger/complicaciones , Síndrome de Zellweger/metabolismo , Temperatura , ATPasas Asociadas con Actividades Celulares Diversas/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Fibroblastos/metabolismo , Mutación/genética
2.
J Med Genet ; 59(3): 220-229, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-33526602

RESUMEN

BACKGROUND: Identifying patients with BRCA mutations is clinically important to inform on the potential response to treatment and for risk management of patients and their relatives. However, traditional referral routes may not meet clinical needs, and therefore, mainstreaming cancer genetics has been shown to be effective in some high-income and high health-literacy settings. To date, no study has reported on the feasibility of mainstreaming in low-income and middle-income settings, where the service considerations and health literacy could detrimentally affect the feasibility of mainstreaming. METHODS: The Mainstreaming Genetic Counselling for Ovarian Cancer Patients (MaGiC) study is a prospective, two-arm observational study comparing oncologist-led and genetics-led counselling. This study included 790 multiethnic patients with ovarian cancer from 23 sites in Malaysia. We compared the impact of different method of delivery of genetic counselling on the uptake of genetic testing and assessed the feasibility, knowledge and satisfaction of patients with ovarian cancer. RESULTS: Oncologists were satisfied with the mainstreaming experience, with 95% indicating a desire to incorporate testing into their clinical practice. The uptake of genetic testing was similar in the mainstreaming and genetics arm (80% and 79%, respectively). Patient satisfaction was high, whereas decision conflict and psychological impact were low in both arms of the study. Notably, decisional conflict, although lower than threshold, was higher for the mainstreaming group compared with the genetics arm. Overall, 13.5% of patients had a pathogenic variant in BRCA1 or BRCA2, and there was no difference between psychosocial measures for carriers in both arms. CONCLUSION: The MaGiC study demonstrates that mainstreaming cancer genetics is feasible in low-resource and middle-resource Asian setting and increased coverage for genetic testing.


Asunto(s)
Oncólogos , Neoplasias Ováricas , Proteína BRCA1/genética , Proteína BRCA2/genética , Consejo , Femenino , Asesoramiento Genético , Pruebas Genéticas/métodos , Humanos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Estudios Prospectivos
3.
J Hum Genet ; 67(3): 169-173, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34531528

RESUMEN

Biallelic variants in ZNF142 at 2q35, which encodes zinc-finger protein 142, cause neurodevelopmental disorder with seizures or dystonia. We identified compound heterozygous null variants in ZNF142, NM_001105537.4:c.[1252C>T];[1274-2A>G],p.[Arg418*];[Glu426*], in Malaysian siblings suffering from global developmental delay with epilepsy and dysmorphism. cDNA analysis showed the marked reduction of ZNF142 transcript level through nonsense-mediated mRNA decay by these novel biallelic variants. The affected siblings present with global developmental delay and epilepsy in common, which were previously described, as well as dysmorphism, which was not recognized. It is important to collect patients with ZNF142 abnormality to define its phenotypic spectrum.


Asunto(s)
Epilepsia , Síndromes Epilépticos , Trastornos del Neurodesarrollo , Niño , Discapacidades del Desarrollo/genética , Epilepsia/genética , Humanos , Trastornos del Neurodesarrollo/genética , Fenotipo , Convulsiones/genética
4.
J Inherit Metab Dis ; 45(4): 769-781, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35279850

RESUMEN

Congenital disorders of glycosylation type 1 (CDG-I) comprise a group of 27 genetic defects with heterogeneous multisystem phenotype, mostly presenting with nonspecific neurological symptoms. The biochemical hallmark of CDG-I is a partial absence of complete N-glycans on transferrin. However, recent findings of a diagnostic N-tetrasaccharide for ALG1-CDG and increased high-mannose N-glycans for a few other CDG suggested the potential of glycan structural analysis for CDG-I gene discovery. We analyzed the relative abundance of total plasma N-glycans by high resolution quadrupole time-of-flight mass spectrometry in a large cohort of 111 CDG-I patients with known (n = 75) or unsolved (n = 36) genetic cause. We designed single-molecule molecular inversion probes (smMIPs) for sequencing of CDG-I candidate genes on the basis of specific N-glycan signatures. Glycomics profiling in patients with known defects revealed novel features such as the N-tetrasaccharide in ALG2-CDG patients and a novel fucosylated N-pentasaccharide as specific glycomarker for ALG1-CDG. Moreover, group-specific high-mannose N-glycan signatures were found in ALG3-, ALG9-, ALG11-, ALG12-, RFT1-, SRD5A3-, DOLK-, DPM1-, DPM3-, MPDU1-, ALG13-CDG, and hereditary fructose intolerance. Further differential analysis revealed high-mannose profiles, characteristic for ALG12- and ALG9-CDG. Prediction of candidate genes by glycomics profiling in 36 patients with thus far unsolved CDG-I and subsequent smMIPs sequencing led to a yield of solved cases of 78% (28/36). Combined plasma glycomics profiling and targeted smMIPs sequencing of candidate genes is a powerful approach to identify causative mutations in CDG-I patient cohorts.


Asunto(s)
Trastornos Congénitos de Glicosilación , Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/genética , Glicómica , Glicosilación , Humanos , Manosa , Manosiltransferasas/genética , N-Acetilglucosaminiltransferasas , Oligosacáridos , Polisacáridos/genética
5.
J Genet Couns ; 31(5): 1080-1089, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35481858

RESUMEN

With the advent of poly-ADP-ribose polymerase inhibitor (PARPi) therapies, the focus of genetic testing for breast, ovarian, and other cancers has shifted from risk management to treatment decision-making in high-resource settings. Due to the shortage of genetic counselors worldwide, alternative ways of delivering genetic counseling have been explored, including training nongenetics healthcare professionals (NGHPs) to provide genetic counseling. However, little is known about the feasibility of adopting such models in healthcare settings with insufficient specialists, where population health literacy is low and where access to new therapies may be limited. In this study, we evaluated the attitudes, considerations, and self-efficacy of oncologists, breast surgeons, and general surgeons in mainstreaming breast cancer genetic counseling in Malaysia, a middle-income Asian country with a universal healthcare system. We developed a 32-item survey via a modified Delphi method, which was then distributed via a purposive and network sampling approach. While 77% of respondents expressed interest in providing breast cancer genetic counseling, 85% preferred to refer patients directly to genetic services for genetic counseling and testing. The main considerations for mainstreaming were the cost of genetic testing and PARPi therapy, as well as the availability of support from genetics professionals. Respondents reported a lack of confidence in communicating genetic risk, particularly to patients with poor health literacy, and in the clinical management of patients with variants of uncertain significance. Our results highlight the urgent need to train more NGHPs in providing genetic counseling and testing in low-to-middle income countries, and suggest that the mainstay for genetic counseling in this setting may be for risk management rather than access to PARPi therapy.


Asunto(s)
Neoplasias de la Mama , Oncólogos , Cirujanos , Adenosina Difosfato Ribosa , Actitud , Neoplasias de la Mama/genética , Femenino , Asesoramiento Genético/métodos , Pruebas Genéticas/métodos , Humanos
6.
Genet Med ; 18(5): 483-93, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-26204423

RESUMEN

PURPOSE: Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established. METHODS: One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians. RESULTS AND CONCLUSION: We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses.Genet Med 18 5, 483-493.


Asunto(s)
Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/genética , Enzimas Reparadoras del ADN/genética , Adolescente , Adulto , Niño , Preescolar , Síndrome de Cockayne/epidemiología , Síndrome de Cockayne/fisiopatología , ADN Helicasas/genética , Reparación del ADN/genética , Femenino , Humanos , Lactante , Masculino , Proteínas de Unión a Poli-ADP-Ribosa , Factores de Transcripción/genética , Adulto Joven
7.
Jpn J Clin Oncol ; 44(5): 506-11, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24683199

RESUMEN

Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder affecting multiple organs. Tuberous sclerosis complex is caused by mutation in either one of the two disease-causing genes, TSC1 or TSC2, encoding for hamartin and tuberin, respectively. TSC2/PKD1 contiguous gene deletion syndrome is a very rare condition due to deletion involving both TSC2 and PKD1 genes. Tuberous sclerosis complex cannot be easily diagnosed since there is no pathognomonic feature, although there are consensus diagnostic criteria for that. Mutation analysis is useful and plays important roles. We report here two novel gross deletions of TSC2 gene in Malay patients with tuberous sclerosis complex and TSC2/PKD1 contiguous gene deletion syndrome, respectively.


Asunto(s)
Pueblo Asiatico/genética , Eliminación de Secuencia , Canales Catiónicos TRPP/genética , Esclerosis Tuberosa/genética , Proteínas Supresoras de Tumor/genética , Adulto , Análisis Mutacional de ADN , Femenino , Humanos , Malasia , Masculino , Síndrome , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa
8.
Eur J Hum Genet ; 2023 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-36973392

RESUMEN

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.

9.
J Clin Invest ; 132(23)2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36282599

RESUMEN

Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy. Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant. TOMM7, a nuclear gene, encodes a translocase in the outer mitochondrial membrane. The TOMM complex makes up the outer membrane pore, which is responsible for importing many preproteins into the mitochondria. A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism. We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts. We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features.


Asunto(s)
Lipodistrofia , Progeria , Humanos , Adulto Joven , Adulto , Progeria/genética , Proteómica , Lipodistrofia/genética , Homocigoto , Exoma , Mutación , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética
10.
PLoS One ; 17(11): e0268149, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36413568

RESUMEN

Classical aniridia is a congenital and progressive panocular disorder almost exclusively caused by heterozygous loss-of-function variants at the PAX6 locus. We report nine individuals from five families with severe aniridia and/or microphthalmia (with no detectable PAX6 mutation) with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. These mutations occurred de novo in 3/5 families, with the remaining families being compatible with autosomal dominant inheritance. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes. Substitutions of the same codon (Arg51) in MAB21L2, a close homolog of MAB21L1, cause severe ocular and skeletal malformations in humans and mice. The predicted nucleotidyltransferase function of MAB21L1 could not be demonstrated using purified protein with a variety of nucleotide substrates and oligonucleotide activators. Induced expression of GFP-tagged wildtype and mutant MAB21L1 in human cells caused only modest transcriptional changes. Mass spectrometry of immunoprecipitated protein revealed that both mutant and wildtype MAB21L1 associate with transcription factors that are known regulators of PAX6 (MEIS1, MEIS2 and PBX1) and with poly(A) RNA binding proteins. Arg51 substitutions reduce the association of wild-type MAB21L1 with TBL1XR1, a component of the NCoR complex. We found limited evidence for mutation-specific interactions with MSI2/Musashi-2, an RNA-binding proteins with effects on many different developmental pathways. Given that biallelic loss-of-function variants in MAB21L1 result in a milder eye phenotype we suggest that Arg51-altering monoallelic variants most plausibly perturb eye development via a gain-of-function mechanism.


Asunto(s)
Aniridia , Microftalmía , Humanos , Animales , Ratones , Microftalmía/genética , Factor de Transcripción PAX6/genética , Aniridia/genética , Mutación Missense , Heterocigoto , Factores de Transcripción/genética , Proteínas de Homeodominio/genética , Proteínas de Unión al ARN/genética , Proteínas del Ojo/genética , Péptidos y Proteínas de Señalización Intracelular/genética
11.
J Inherit Metab Dis ; 33 Suppl 3: S489-95, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21161389

RESUMEN

Citrin deficiency, aetiologically linked to mutations of SLC25A13 gene, has two clinical phenotypes, namely adult-onset type II citrullinaemia (CTLN2) and neonatal/infantile intrahepatic cholestasis, caused by citrin deficiency (NICCD). Malaysian patients with NICCD, especially of Malay and East Malaysian indigenous descent, have never been reported in the literature. We present the clinical features, biochemical findings and results of molecular analysis in 11 Malaysian children with NICCD. In this case series, all patients manifested prolonged cholestatic jaundice and elevated citrulline levels. The other more variable features included failure to thrive, bleeding diathesis, hypoproteinaemia, abnormal liver enzymes, prolonged coagulation profile, hyperammonaemia, hypergalactosaemia, multiple aminoacidaemia, elevated α-feto protein and urinary orotic acid as well as liver biopsies showing hepatitis and steatosis. DNA analysis of SLC25A13 revealed combinations of 851del4(Ex9), IVS16ins3kb and 1638ins23. Most of our patients recovered completely by the age of 22 months. However, one patient had ongoing symptoms at the time of reporting and one had died of liver failure. Since a small percentage of children with NICCD will develop CTLN2 and the mechanisms leading to this is yet to be defined, ongoing health surveillance into adulthood is essential.


Asunto(s)
Citrulinemia , Pueblo Asiatico/genética , Biomarcadores/sangre , Citrulina/sangre , Citrulinemia/complicaciones , Citrulinemia/diagnóstico , Citrulinemia/etnología , Citrulinemia/genética , Citrulinemia/metabolismo , Citrulinemia/terapia , Análisis Mutacional de ADN , Exones , Resultado Fatal , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Lactante , Recién Nacido , Ictericia Obstructiva/etiología , Fallo Hepático/etiología , Malasia/epidemiología , Masculino , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Mutación , Linaje , Fenotipo , Pronóstico , Factores de Tiempo
12.
Genes Genomics ; 41(8): 885-893, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31028654

RESUMEN

BACKGROUND: Glycogen storage disease type III is an autosomal recessive disorder that is caused by deficiencies of the glycogen debranching enzyme. Mutations within the AGL gene have been found to be heterogeneous, with some common mutations being reported in certain populations. The mutation spectrum of AGL gene in the multi-ethnic Malaysian population is still unknown. OBJECTIVE: The present study seeks to determine the mutation spectrum of the AGL gene in Malaysian population. METHODS: A total of eleven patients (eight Malay, two Chinese and one Bajau) were investigated. Genomic DNA was extracted and subsequently the AGL gene was amplified using specific primers and sequenced. Mutations found were screened in 150 healthy control samples either by restriction enzyme digestion assay or TaqMan® SNP Genotyping assay. RESULTS: We identified six unreported mutations (c.1423+1G>T, c.2914_2915delAA, c.3814_3815delAG, c.4333T>G, c.4490G>A, c.4531_4534delTGTC) along with three previously reported mutations (c.99C>T, c.1783C>T, c.2681+1G>A). One of the six unreported mutation causes abnormal splicing and results in retention of intron 12 of the mature transcript, while another is a termination read-through. One of the reported mutation c.2681+1G>A was recurrently found in the Malay patients (n = 7 alleles; 31.8%). CONCLUSION: The mutation spectrum of the AGL gene in Malaysian patients has shown considerable heterogeneity, and all unreported mutations were absent in all 150 healthy control samples tested.


Asunto(s)
Sistema de la Enzima Desramificadora del Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno Tipo III/genética , Mutación , Niño , Preescolar , Femenino , Sistema de la Enzima Desramificadora del Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo III/patología , Humanos , Lactante , Intrones , Masculino , Empalme del ARN
13.
Orphanet J Rare Dis ; 14(1): 143, 2019 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-31200731

RESUMEN

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disease due to N-acetylgalactosamine-6-sulfatase (GALNS) deficiency. It results in accumulation of the glycosaminoglycans, keratan sulfate and chondroitin-6-sulfate, leading to skeletal and other systemic impairments. Data on MPS IVA in Asian populations are scarce. METHODS: This is a multicentre descriptive case series of 21 patients comprising all MPS IVA patients in Malaysia. Mutational analysis was performed by PCR and Sanger sequencing of the GALNS gene in 17 patients. RESULTS: The patients (15 females and 6 males) had a mean age (± SD) of 15.5 (± 8.1) years. Mean age at symptom onset was 2.6 (± 2.1) years and at confirmed diagnosis was 6.9 (± 4.5) years. The study cohort included patients from all the main ethnic groups in Malaysia - 57% Malay, 29% Chinese and 14% Indian. Common presenting symptoms included pectus carinatum (57%) and genu valgum (43%). Eight patients (38%) had undergone surgery, most commonly knee surgeries (29%) and cervical spine decompression (24%). Patients had limited endurance with lower mean walking distances with increasing age. GALNS gene analysis identified 18 distinct mutations comprising 13 missense, three nonsense, one small deletion and one splice site mutation. Of these, eight were novel mutations (Tyr133Ser, Glu158Valfs*12, Gly168*, Gly168Val, Trp184*, Leu271Pro, Glu320Lys, Leu508Pro). Mutations in exons 1, 5 and 9 accounted for 51% of the mutant alleles identified. CONCLUSIONS: All the MPS IVA patients in this study had clinical impairments. A better understanding of the natural history and the clinical and genetic spectrum of MPS IVA in this population may assist early diagnosis, improve management and permit timely genetic counselling and prenatal diagnosis.


Asunto(s)
Mucopolisacaridosis IV/genética , Mucopolisacaridosis IV/patología , Adolescente , Adulto , Niño , Preescolar , Condroitinsulfatasas/genética , Condroitinsulfatasas/metabolismo , Estudios de Cohortes , Femenino , Humanos , Malasia , Masculino , Mucopolisacaridosis IV/metabolismo , Adulto Joven
14.
Pediatr Neonatol ; 59(4): 397-403, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29203193

RESUMEN

BACKGROUND: Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare autosomal recessive inborn error of gluconeogenesis. We reported the clinical findings and molecular genetic data in seven Malaysian patients with FBPase deficiency. METHODS: All patients diagnosed with FBPase deficiency from 2010 to 2015 were included in this study. Their clinical and laboratory data were collected retrospectively. RESULTS: All the patients presented with recurrent episodes of hypoglycemia, metabolic acidosis, hyperlactacidemia and hepatomegaly. All of them had the first metabolic decompensation prior to 2 years old. The common triggering factors were vomiting and infection. Biallelic mutations in FBP1 gene (MIM*611570) were identified in all seven patients confirming the diagnosis of FBPase deficiency. In four patients, genetic study was prompted by detection of glycerol or glycerol-3-phosphate in urine organic acids analysis. One patient also had pseudo-hypertriglyceridemia. Seven different mutations were identified in FBP1, among them four mutations were new: three point deletions (c.392delT, c.603delG and c.704delC) and one splice site mutation (c.568-2A > C). All four new mutations were predicted to be damaging by in silico analysis. One patient presented in the neonatal period and succumbed due to sepsis and multi-organ failure. Among six survivors (current age ranged from 4 to 27 years), four have normal growth and cognitive development. One patient had short stature and another had neurological deficit following status epilepticus due to profound hypoglycemia. CONCLUSION: FBPase deficiency needs to be considered in any children with recurrent hypoglycemia and metabolic acidosis. Our study expands the spectrum of FBP1 gene mutations.


Asunto(s)
Acidosis/etiología , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Deficiencia de Fructosa-1,6-Difosfatasa/complicaciones , Hipoglucemia/etiología , Mutación , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Proteínas de Unión al ARN , Recurrencia , Estudios Retrospectivos
15.
J Mol Diagn ; 19(2): 265-276, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28087349

RESUMEN

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by tumor growth in multiple organs and caused by mutations in either TSC1 or TSC2 genes. Because of their relatively large genomic sizes, absence of hotspots, and common type of mutations, mutation detection in TSC1 and TSC2 genes has been challenging. We devised a combination of multiple ligation-dependent probe amplification (MLPA) and amplicon sequencing (AS) to simplify the detection strategy, yet we come up with reasonably high detection rate. Thirty-four Malaysian patients diagnosed with TSC were referred to Human Genome Center, Universiti Sains Malaysia. We used a combination of MLPA to detect large copy number changes and AS to detect smaller mutations. TSC1 pathogenic or likely pathogenic mutations were found in 6 patients (18%) and TSC2 in 21 patients (62%), whereas 6 patients (18%) show no mutations and 1 patient (2%) showed only TSC2 missense variant with uncertain significance. Six of the mutations are novel. Our detection strategy costs 81% less and require 1 working week less than the conventional strategy. Confirmatory sequencing using Sanger method on a few representative mutations showed agreement with results of the AS. Combination of MLPA and Illumina MiSeq AS provides a simplified strategy and reasonably high detection rate for TSC1/TSC2 mutation, which suggested application of the strategies into clinical molecular diagnostics.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Técnicas de Amplificación de Ácido Nucleico , Esclerosis Tuberosa/diagnóstico , Esclerosis Tuberosa/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Niño , Preescolar , Estudios Transversales , Análisis Mutacional de ADN/métodos , Femenino , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento/economía , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Humanos , Lactante , Masculino , Persona de Mediana Edad , Técnicas de Amplificación de Ácido Nucleico/economía , Técnicas de Amplificación de Ácido Nucleico/métodos , Técnicas de Amplificación de Ácido Nucleico/normas , Fenotipo , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa , Adulto Joven
17.
J Pediatr Endocrinol Metab ; 29(9): 1031-9, 2016 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-27544719

RESUMEN

BACKGROUND: The aim of this study was to determine the feasibility of performing newborn screening (NBS) of inborn errors of metabolism (IEMs) using tandem mass spectrometry (TMS) and the impact on its detection rate in Malaysia. METHODS: During the study period between June 2006 and December 2008, 30,247 newborns from 11 major public hospitals in Malaysia were screened for 27 inborn errors of amino acid, organic acid and fatty acid metabolism by TMS. Dried blood spot (DBS) samples were collected between 24 h and 7 days with parental consent. Samples with abnormal results were repeated and the babies were recalled to confirm the diagnosis with follow-up testing. RESULTS: Cut-off values for amino acids and acylcarnitines were established. Eight newborns were confirmed to have IEM: two newborns with Maple syrup urine disease (MSUD), two with methylmalonic aciduria (MMA) one with ethylmalonic aciduria, two with argininosuccinic aciduria and one with isovaleric aciduria. Diagnosis was missed in two newborns. The detection rate of IEMs in this study was one in 2916 newborns. The sensitivity and specificity of TMS were 80% and 99%, respectively. CONCLUSIONS: IEMs are common in Malaysia. NBS of IEMs by TMS is a valuable preventive strategy by enabling the diagnosis and early treatment of IEM before the onset of symptoms aiming at prevention of mental retardation and physical handicap. A number of shortcomings warrant further solution so that in near future NBS for IEMs will become a standard of care for all babies in Malaysia in tandem with the developed world.


Asunto(s)
Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/epidemiología , Tamizaje Neonatal/métodos , Espectrometría de Masas en Tándem/métodos , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Malasia/epidemiología , Masculino , Proyectos Piloto , Pronóstico
18.
Nat Commun ; 7: 10822, 2016 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-26905694

RESUMEN

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.


Asunto(s)
Cadherinas/genética , Adhesión Celular/genética , Movimiento Celular/genética , Fibroblastos/metabolismo , Síndrome Nefrótico/congénito , Podocitos/metabolismo , Proteínas de Pez Cebra/genética , Animales , Dilatación Patológica/genética , Técnicas de Silenciamiento del Gen , Hematuria/genética , Humanos , Túbulos Renales/citología , Túbulos Renales/metabolismo , Túbulos Renales/patología , Lisencefalia/genética , Ratones , Mutación , Síndrome Nefrótico/genética , Síndrome , Pez Cebra , Proteína de Unión al GTP cdc42/metabolismo , Proteína de Unión al GTP rac1/metabolismo
19.
Pediatr Neurol ; 49(3): 185-90, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23835273

RESUMEN

BACKGROUND: X-linked adrenoleukodystrophy is caused by a defective peroxisomal membrane transporter, ABCD1, responsible for transporting very-long-chain fatty acid substrate into peroxisomes for degradation. The main biochemical defect, which is also one of the major diagnostic hallmarks, of X-linked adrenoleukodystrophy is the accumulation of saturated very-long-chain fatty acids in all tissues and body fluids. METHODS: Direct and reverse-transcribed polymerase chain reactions followed by DNA sequencing-based mutational analyses were performed on one Taiwanese and three Malaysian X-linked adrenoleukodystrophy families. RESULTS: A novel splicing donor site mutation (c.1272+1g>a) was identified in a Taiwanese X-linked adrenoleukodystrophy patient, resulting in a deletion of 121 bp and a premature stop codon (p.Val425fs*92) in messenger-RNA transcript. This deletion is caused by the activation of a cryptic splicing donor site in exon 4 of the ABCD1 gene, which is consistent with the prediction by several online algorithms. In addition, three previously described missense mutations (c.965T>C, c.1978C>T, and c.2006A>G), leading to aberrant ABCD1 of p.Leu322Pro, p.Arg660Trp, and p.His669Arg, were also identified in Malaysian probands. CONCLUSIONS: This is the first report to unveil unequivocally that cryptic splicing-induced aberrant messenger-RNA carrying an internal frameshift deletion results from an intronic mutation in the ABCD1 gene. Furthermore, a polymorphism in intron 9 (c.1992-32c/t; refSNP: rs4898368) of the ABCD1 gene was commonly observed in both Taiwanese and Malaysian populations.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Adrenoleucodistrofia/genética , Predisposición Genética a la Enfermedad/genética , Mutación Missense/genética , Eliminación de Secuencia , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Análisis Mutacional de ADN , Exones/genética , Femenino , Humanos , Imagen por Resonancia Magnética , Malasia , Masculino , Análisis Numérico Asistido por Computador , Taiwán
20.
Eur J Med Genet ; 54(6): e553-9, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21816239

RESUMEN

We describe the clinical characteristics of 4 singleton cases, 3 males and 1 female, with Myhre Syndrome (OMIM 139210), who were born to non-consanguineous parents. Three cases had no family history of similarly affected individuals but 1 male's mother had short stature, some facial features suggestive of Myhre syndrome and evidence of skewed X-chromosome inactivation in her blood DNA. Short stature, deafness, learning difficulties, skeletal anomalies and facial dysmorphisms were evident in all cases. Arthralgia and stiff joints with limited movement were also present. The facial appearance, thickened skin, a 'muscular' habitus are memorable features. The female patient was least affected: this patient and one affected male displayed streaky skin with areas of patchy thickening, suggestive of genetic mosaicism. One patient developed sleep apnoea, a restrictive ventilatory defect and died following a choking episode. Another affected male developed recurrent, progressive, proximal, tracheal stenosis requiring partial tracheal resection, laser treatment and eventually tracheotomy. Review of Myhre syndrome patients in the literature and syndromes in the differential diagnosis, suggests heterogeneity in Myhre syndrome and clinical overlap with Laryngotracheal stenosis, Arthropathy, Prognathism and Short stature syndrome.


Asunto(s)
Anomalías Múltiples/diagnóstico , Criptorquidismo , Facies , Trastornos del Crecimiento , Deformidades Congénitas de la Mano , Hipertrofia , Discapacidad Intelectual , Artropatías , Sistema Respiratorio/patología , Adolescente , Adulto , Criptorquidismo/diagnóstico , Criptorquidismo/genética , Criptorquidismo/patología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/patología , Deformidades Congénitas de la Mano/diagnóstico , Deformidades Congénitas de la Mano/genética , Deformidades Congénitas de la Mano/patología , Humanos , Hipercalcemia/diagnóstico , Hipertrofia/diagnóstico , Hipertrofia/genética , Hipertrofia/patología , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Artropatías/diagnóstico , Artropatías/genética , Artropatías/patología , Laringoestenosis/diagnóstico , Masculino , Enfermedades Metabólicas/diagnóstico , Nefrocalcinosis/diagnóstico , Linaje , Prognatismo/diagnóstico , Anomalías Cutáneas/patología , Estenosis Traqueal/diagnóstico , Reino Unido , Inactivación del Cromosoma X
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