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1.
Thromb Haemost ; 119(9): 1461-1470, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31352676

RESUMO

Bernard-Soulier syndrome (BSS) is a hereditary macrothrombocytopenia caused by defects in the glycoprotein (GP) Ib-IX-V complex. The mechanism of giant platelet formation remains undefined. Currently, megakaryocytes (MKs) can be generated from induced pluripotent stem cells (iPSCs) to study platelet production under pharmacological or genetic manipulations. Here, we generated iPSC lines from two BSS patients with mutations in different genes (GP1BA and GP1BB: termed BSS-A and BSS-B, respectively). The iPSC-derived MKs and platelets were examined under electron microscopy and stained by immunofluorescence to observe proplatelet formation and measure platelet diameters which were defined by circumferential tubulin. BSS-iPSCs produced abnormal proplatelets with thick shafts and tips. In addition, compared with the normal iPSCs, the diameters were larger in platelets derived from BSS-A and BSS-B with the means ± standard deviations of 4.34 ± 0.043 and 3.88 ± 0.045 µm, respectively (wild-type iPSCs 2.61 ± 0.025 µm, p < 0.001). Electron microscopy revealed giant platelets with the abnormal demarcation membrane system. Correction of BSS-A and BSS-B-iPSCs using lentiviral vectors containing respective GP1BA and GP1BB genes improved proplatelet structures and platelet ultrastructures as well as reduced platelets sizes. In conclusion, the iPSC model can be used to explore molecular mechanisms and potential therapy for BSS.

2.
Stem Cell Res ; 39: 101493, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31326747

RESUMO

Two clones of human induced pluripotent stem cells (iPSCs) were generated from dermal fibroblasts isolated from a one-year-old Thai patient with X-linked osteogenesis imperfecta. The patient harbored a mutation, p.N459S, in the MBTPS2 gene. The cells were reprogrammed using an integration-free Sendai virus containing KLF4, c-MYC, OCT4 and SOX2. Both of the established iPSC lines (MDCUi001-A and MDCUi001-B) maintained normal karyotype, expressed pluripotent markers and differentiated into all three germ layers.

3.
Horm Res Paediatr ; : 1-7, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362300

RESUMO

Infantile Cushing's syndrome is potentially found as part of McCune-Albright syndrome (MAS) which is caused by postzygotic somatic mutations of the GNAS gene. MAS is typically characterized by a triad of polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and precocious puberty or other endocrine hyperfunction. Here, we describe a 2-month-old female infant with features of Cushing's syndrome without café au lait spots, polyostotic fibrous dysplasia, and clinical evidence of other endocrine hyperfunction. Investigations demonstrated adrenocorticotropic hormone-independent Cushing's syndrome with bilateral adrenal gland enlargement. Whole-exome sequencing of leukocytes identified a de novo heterozygous novel missense mutation (c.521G>A, p.Cys174Tyr) in the GNAS gene. The patient experienced clinical improvement of Cushing's syndrome during ketoconazole treatment. Her clinical course was complicated by Pneumocystis jiroveci pneumonia. She also had shortened activated partial thromboplastin time indicating a hypercoagulable state and resulting in pulmonary embolism. She eventually manifested gonadotropin-independent precocious puberty at the age of 13 months after ketoco-nazole was discontinued. This patient demonstrated that Cushing syndrome can be the presenting sign of MAS in infancy. A high index of suspicion followed by genetic analysis is essential in order to establish a diagnosis.

6.
Mol Genet Genomics ; 294(3): 773-787, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30887145

RESUMO

The latent transforming growth factor-beta-binding protein 3 (LTBP3), encoding extracellular matrix proteins, plays a role in skeletal formation. Mutations in LTBP3 have been associated with various types of skeletal dysplasia. We aimed to characterize clinical and molecular features of more patients with mutations in the gene, which may help suggest genotype-phenotype correlation. The first two East Asian patients with short stature, heart defects, and orodental anomalies having LTBP3 mutations were identified. Whole exome and Sanger sequencing revealed that the one with a novel heterozygous missense (c.2017G>T, p.Gly673Cys) mutation in LTBP3 had clinical features consistent with acromicric dysplasia (ACMICD). The variant was located in the highly conserved EGF-like calcium-binding domain adjacent to the single reported LTBP3 variant associated with ACMICD. This finding supports that LTBP3 is a disease gene for ACMICD. Another patient with a novel homozygous splice site acceptor (c.1721-2A>G) mutation in LTBP3 was affected with dental anomalies and short stature (DASS). Previously undescribed orodental features included multiple unerupted teeth, high-arched palate, and microstomia found in our patient with ACMICD, and extensive dental infection, condensing osteitis, and deviated alveolar bone formation in our patient with DASS. Our results and comprehensive reviews suggest a genotype-phenotype correlation: biallelic loss-of-function mutations cause DASS, monoallelic missense gain-of-function mutations in the EGF-like domain cause ACMICD, and monoallelic missense gain-of-function mutations with more drastic effects on the protein functions cause geleophysic dysplasia (GPHYSD3). In summary, we expand the phenotypic and genotypic spectra of LTBP3-related disorders, support that LTBP3 is a disease gene for ACMICD, and propose the genotype-phenotype correlation of LTBP3 mutations.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Estudos de Associação Genética/métodos , Proteínas de Ligação a TGF-beta Latente/genética , Deformidades Congênitas dos Membros/genética , Mutação , Anormalidades Dentárias/genética , Adolescente , Sequência de Aminoácidos , Criança , Nanismo/genética , Feminino , Humanos , Masculino , Linhagem , Homologia de Sequência de Aminoácidos , Adulto Jovem
7.
Gene ; 696: 21-27, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30771478

RESUMO

Intellectual disabilities (ID) are etiologically heterogeneous. Advanced molecular techniques could be helpful in identification of the underlying genetic defects. We aimed to characterize clinical and molecular features of three Thai patients with ID. Patient 1 had ID, hypotonia and lactic acidosis. Patient 2 had ID and growth failure. Patient 3 had ID, seizure, diarrhea and hypoglycemia. Whole exome sequencing found that Patient 1 was homozygous for a nonsense, c.1303C>T (p.Arg435Ter), mutation in FBXL4, a gene responsible for encephalomyopathic mitochondrial DNA depletion syndrome-13 (MTDPS13). Patient 2 was compound heterozygous for two novel mutations, c.3226C>T (p.Arg1076Ter) and c.3205C>T (p.Arg1069Ter), in UNC80, a known gene of infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2). Patient 3 was homozygous for a novel missense, c.427T>C (p.Cys143Arg), mutation in ADK, a known gene of adenosine kinase deficiency leading to hypermethioninemia. This study expands the mutational spectra of ID genes.


Assuntos
Adenosina Quinase/genética , Proteínas de Transporte/genética , Proteínas F-Box/genética , Testes Genéticos/métodos , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Ubiquitina-Proteína Ligases/genética , Feminino , Homozigoto , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Mutação , Índice de Gravidade de Doença , Tailândia , Sequenciamento Completo do Exoma
8.
PLoS Genet ; 14(11): e1007817, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30475797

RESUMO

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.

9.
Gene ; 679: 377-381, 2018 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-30223008

RESUMO

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder affecting both males and females. Hemizygous males commonly present with severe hyperammonemic encephalopathy during the neonatal period. Heterozygous females have great phenotypic variability. The majority of female patients can manifest later in life or have unrecognized symptoms, making the diagnosis of OTCD in females very challenging. Here we report on three unrelated Thai female cases with OTCD presenting with different manifestations including aggressive behavior, acute liver failure and severe encephalopathy. Whole exome sequencing successfully identified disease-causing mutations in all three cases including two novel ones: the c.209_210delAA (p.Lys70Argfs*17) and the c.850T>A (p.Tyr284Asn). This study affirms variable symptoms in female patients with OTCD and emphasizes the importance of early recognition and prompt management for favorable outcomes. In addition, identification of two novel causative variants expands the genotypic spectrum of OTC.


Assuntos
Mutação , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Ornitina Carbamoiltransferase/genética , Sequenciamento Completo do Exoma/métodos , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Linhagem , Tailândia
11.
PLoS One ; 13(7): e0201071, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30036398

RESUMO

BACKGROUND: The exact cause and mechanisms underlying the pathobiology of autism spectrum disorder (ASD) remain unclear. Dysregulation of long interspersed element-1 (LINE-1) has been reported in the brains of ASD-like mutant mice and ASD brain tissues. However, the role and methylation of LINE-1 in individuals with ASD remain unclear. In this study, we aimed to investigate whether LINE-1 insertion is associated with differentially expressed genes (DEGs) and to assess LINE-1 methylation in ASD. METHODS: To identify DEGs associated with LINE-1 in ASD, we reanalyzed previously published transcriptome profiles and overlapped them with the list of LINE-1-containing genes from the TranspoGene database. An Ingenuity Pathway Analysis (IPA) of DEGs associated with LINE-1 insertion was conducted. DNA methylation of LINE-1 was assessed via combined bisulfite restriction analysis (COBRA) of lymphoblastoid cell lines from ASD individuals and unaffected individuals, and the methylation levels were correlated with the expression levels of LINE-1 and two LINE-1-inserted DEGs, C1orf27 and ARMC8. RESULTS: We found that LINE-1 insertion was significantly associated with DEGs in ASD. The IPA showed that LINE-1-inserted DEGs were associated with ASD-related mechanisms, including sex hormone receptor signaling and axon guidance signaling. Moreover, we observed that the LINE-1 methylation level was significantly reduced in lymphoblastoid cell lines from ASD individuals with severe language impairment and was inversely correlated with the transcript level. The methylation level of LINE-1 was also correlated with the expression of the LINE-1-inserted DEG C1orf27 but not ARMC8. CONCLUSIONS: In ASD individuals with severe language impairment, LINE-1 methylation was reduced and correlated with the expression levels of LINE-1 and the LINE-1-inserted DEG C1orf27. Our findings highlight the association of LINE-1 with DEGs in ASD blood samples and warrant further investigation. The molecular mechanisms of LINE-1 and the effects of its methylation in ASD pathobiology deserve further study.

12.
BMC Med Genet ; 19(1): 117, 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30012084

RESUMO

BACKGROUND: WNT1 mutations cause bone fragility as well as brain anomalies. There are some reported cases of WNT1 mutations with normal cognition. Genotype and phenotype correlation of WNT1 mutations has not been established. CASE PRESENTATION: Here we present two female siblings with osteogenesis imperfecta (OI) born to a consanguineous couple. Both sustained severe bone deformities. However, only the younger had severe brain anomalies resulting in an early death from pneumonia, while the older had normal intellectual development. Next generation sequencing showed a homozygous mutation, c.6delG, p.Leu3Serfs*36 in WNT1. To our knowledge, it is the most 5' truncating mutation to date. CONCLUSION: This report emphasizes the intrafamilial variability of brain anomalies found in this OI type and suggests that WNT1 may not be necessary for normal human cognitive development.

13.
J Nutr Metab ; 2018: 5124035, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29854440

RESUMO

Background: Age, race, and analytic method influence levels of blood amino acids, of which reference intervals are required for the diagnosis and management of inherited metabolic disorders. Objectives: To establish age-specific reference intervals for blood amino acids in Thai pediatric population measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Methods: A cross-sectional study of 277 healthy children from birth to 12 years was conducted. Anthropometric, clinical, and dietary information were recorded. Dried blood spots on a filtered paper were used for measurement by derivatized LC-MS/MS. Factors that might affect amino acids such as fasting time and dietary intake were analyzed using quantile regression analysis. Results: Levels of thirteen blood amino acids were reported as median and interval from 2.5th-97.5th percentiles. Compared with those of Caucasian, most blood amino acid levels of Thai children were higher. Compared with a previous study using HPLC in Thai children, many amino acid levels are different. Glycine, alanine, leucine/isoleucine, and glutamic acid sharply decreased after birth. Citrulline, arginine, and methionine stayed low from birth throughout childhood, whereas phenylalanine was at middle level and slightly increased during preadolescence. Conclusion: Reference intervals of age-specific blood amino acids using LC-MS/MS were established in the Thai pediatric population. They diverge from previous studies, substantiating the recommendation that, for the optimal clinical practice, age-specific reference intervals of amino acids should be designated for the particular population and analysis method.

14.
Br J Ophthalmol ; 102(9): 1303-1307, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29706602

RESUMO

BACKGROUND: Polymorphisms in human leucocyte antigen (HLA) class I genes have been found to be associated with cold medicine (CM)-related Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with severe ocular complications (SOC). Because ethnic differences in genetic predisposition to SJS/TEN among different populations have been proposed, we focused on Thai patients and investigated the association between HLA class I genotypes and CM-SJS/TEN with SOC. METHODS: This multicentre case-control study was conducted between September 2014 and August 2017. Seventy-one Thai patients with SJS/TEN with SOC and 159 healthy Thai controls were enrolled. HLA typing was performed. Genetic relationships were analysed using Fisher's exact test. RESULTS: Of 71 patients with SJS/TEN with SOC (28 male, 43 female), 49 (69%) had a history of taking cold medications prior to SJS/TEN onset. The mean age of onset was 26.7±17.1 years (range, 2-77 years). HLA-B*44:03 (OR, 7.2, p=5.5×10-6, pc=1.1×10-4) and HLA-C*07:01 (OR, 6.1, p=7.1×10-6, pc=1.1×10-4) showed significant positive associations with Thai patients with CM-SJS/TEN with SOC. Additionally, 17 of 49 patients with CM-SJS/TEN with SOC (34.7%) significantly harboured the HLA-B*44:03 and HLA-C*07:01 haplotype compared with only 11 of 159 healthy controls (6.9%) (OR=7.1, p=5.5×10-6). CONCLUSIONS: HLA-B*44:03-HLA-C*07:01 haplotype is a potential risk factor for CM-SJS/TEN with SOC in the Thai population. This study supports that HLA-B*44:03 might be a common marker for CM-SJS/TEN with SOC in Eurasia populations, including European, Indian, Japanese and Thai.

15.
Int J Biol Sci ; 14(4): 381-389, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29725259

RESUMO

Kabuki syndrome is a rare genetic disorder characterized by distinct dysmorphic facial features, intellectual disability, and multiple developmental abnormalities. Despite more than 350 documented cases, the oro-dental spectrum associated with kabuki syndrome and expression of KMT2D (histone-lysine N-methyltransferase 2D) or KDM6A (lysine-specific demethylase 6A) genes in tooth development have not been well defined. Here, we report seven unrelated Thai patients with Kabuki syndrome having congenital absence of teeth, malocclusion, high-arched palate, micrognathia, and deviated tooth shape and size. Exome sequencing successfully identified that six patients were heterozygous for mutations in KMT2D, and one in KDM6A. Six were novel mutations, of which five were in KMT2D and one in KDM6A. They were truncating mutations including four frameshift deletions and two nonsense mutations. The predicted non-functional KMT2D and KDM6A proteins are expected to cause disease by haploinsufficiency. Our study expands oro-dental, medical, and mutational spectra associated with Kabuki syndrome. We also demonstrate for the first time that KMT2D and KDM6A are expressed in the dental epithelium of human tooth germs.

16.
Skeletal Radiol ; 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29744569

RESUMO

Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) (OMIM 614875) is a severe chondrodysplasia combined with a urinary excretion of D-2-hydroxyglutaric acid. Here, we reported the tenth case of this disease. A 15-year-old boy had symmetric radiolulencies in the metaphyses of the long bones suggesting enchondromatosis and platyspondyly. Remarkably, he manifested widespread cavernous hemangiomas including scalp, lips, tongue, larynx, and prepuce, with the onset of 3 years of age. Hemangiomas at the larynx had caused dyspnea and those in the oral cavity led to recurrent bleeding, requiring several surgical removals. These multiple and debilitating hemangiomas have never been previously reported in patients with MC-HGA. Mutation analyses including Sanger sequencing of genes involving in enchondromatosis and the metabolic pathway of D-2-hydroxyglutarate including PTHR1, D2HGDH, HOT, and IDH1, as well as whole-exome sequencing for proband-parent trio analysis and paired blood versus hemangioma studies showed no pathogenic variants. In summary, we reported the tenth patient with MC-HGA who manifested widespread and debilitating hemangiomas in several organs, expanding the clinical spectrum of MC-HGA.

17.
Mol Autism ; 9: 27, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29686828

RESUMO

Background: Alu elements are a group of repetitive elements that can influence gene expression through CpG residues and transcription factor binding. Altered gene expression and methylation profiles have been reported in various tissues and cell lines from individuals with autism spectrum disorder (ASD). However, the role of Alu elements in ASD remains unclear. We thus investigated whether Alu elements are associated with altered gene expression profiles in ASD. Methods: We obtained five blood-based gene expression profiles from the Gene Expression Omnibus database and human Alu-inserted gene lists from the TranspoGene database. Differentially expressed genes (DEGs) in ASD were identified from each study and overlapped with the human Alu-inserted genes. The biological functions and networks of Alu-inserted DEGs were then predicted by Ingenuity Pathway Analysis (IPA). A combined bisulfite restriction analysis of lymphoblastoid cell lines (LCLs) derived from 36 ASD and 20 sex- and age-matched unaffected individuals was performed to assess the global DNA methylation levels within Alu elements, and the Alu expression levels were determined by quantitative RT-PCR. Results: In ASD blood or blood-derived cells, 320 Alu-inserted genes were reproducibly differentially expressed. Biological function and pathway analysis showed that these genes were significantly associated with neurodevelopmental disorders and neurological functions involved in ASD etiology. Interestingly, estrogen receptor and androgen signaling pathways implicated in the sex bias of ASD, as well as IL-6 signaling and neuroinflammation signaling pathways, were also highlighted. Alu methylation was not significantly different between the ASD and sex- and age-matched control groups. However, significantly altered Alu methylation patterns were observed in ASD cases sub-grouped based on Autism Diagnostic Interview-Revised scores compared with matched controls. Quantitative RT-PCR analysis of Alu expression also showed significant differences between ASD subgroups. Interestingly, Alu expression was correlated with methylation status in one phenotypic ASD subgroup. Conclusion: Alu methylation and expression were altered in LCLs from ASD subgroups. Our findings highlight the association of Alu elements with gene dysregulation in ASD blood samples and warrant further investigation. Moreover, the classification of ASD individuals into subgroups based on phenotypes may be beneficial and could provide insights into the still unknown etiology and the underlying mechanisms of ASD.


Assuntos
Elementos Alu , Transtorno do Espectro Autista/genética , Metilação de DNA , Epigênese Genética , Redes Reguladoras de Genes , Transcriptoma , Estudos de Casos e Controles , Células Cultivadas , Feminino , Genoma Humano , Humanos , Masculino
18.
Clin Oral Investig ; 2018 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-29679229

RESUMO

OBJECTIVES: Dentin sialophosphoprotein (DSPP) plays an important role in the mineralization of both dentin and bones. The Dspp null mice developed periodontal diseases. Patients with DSPP mutations have dentinogenesis imperfecta (DGI), but very little is known about their bone characteristics. This study aims to characterize alveolar bone cells of a DGI patient with DSPP mutation. MATERIALS AND METHODS: Pathogenic variants were identified by whole exome and sanger sequencing. Cells isolated from the alveolar bones of a DSPP patient were investigated for their characteristics including cell morphology, attachment, spreading, proliferation, colony formation, mineralization, and osteogenic differentiation. RESULTS: We identified a Thai family with three members affected with autosomal dominant DGI harboring a heterozygous pathogenic missense mutation, c.50C > T, p.P17L, in exon 2 of the DSPP gene. The patients' phenotypes presented deteriorated opalescent teeth with periapical lesions, thickening of lamina dura, furcation involvement, alveolar bone loss, and bone exostoses. The alveolar bone cells isolated from DSPP patient exhibited compromised proliferation and colony formation. Scanning electron microscope revealed altered cellular morphology and spreading. The DSPP cells showed deviated mRNA levels of OCN, ALP, and COL1 but maintained in vitro mineralization ability compared to the control. CONCLUSIONS: We demonstrate that the DSPP p.P17L mutant alveolar bone cells had compromised cell spreading, proliferation, colony formation, and osteogenic induction, suggesting abnormal bone characteristics in the patient with DGI caused by DSPP mutation. CLINICAL RELEVANCE: DSPP mutation can induce the behavior alterations of alveolar bone cells.

19.
Case Rep Dermatol Med ; 2017: 3905658, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29209542

RESUMO

Introduction: Maple syrup urine disease (MSUD) is an inborn error of branched chain amino acids (BCAAs) metabolism. We report an infant with MSUD who developed 2 episodes of cutaneous lesions as a result of isoleucine deficiency and zinc deficiency, respectively. Case Presentation: A 12-day-old male infant was presented with poor milk intake and lethargy. The diagnosis of MSUD was made based on clinical and biochemical data. Management and Outcome: Specific dietary restriction of BCAAs was given. Subsequently, natural protein was stopped as the patient developed hospital-acquired infections which resulted in an elevation of BCAAs. Acrodermatitis dysmetabolica developed and was confirmed to be from isoleucine deficiency. At the age of 6 months, the patient developed severe lethargy and was on natural protein exclusion for an extended period. Despite enteral supplementation of zinc sulfate, cutaneous manifestations due to zinc deficiency occurred. Discussion: Skin lesions in MSUD patients could arise from multiple causes. Nutritional deficiency including isoleucine and zinc deficiencies can occur and could complicate the treatment course as a result of malabsorption, even while on enteral supplementation. Parenteral nutrition should be considered and initiated accordingly. Clinical status, as well as BCAA levels, should be closely monitored in MSUD patients.

20.
Genet. mol. biol ; 40(4): 763-767, Oct.-Dec. 2017. graf
Artigo em Inglês | LILACS-Express | ID: biblio-892453

RESUMO

Abstract Osteogenesis imperfecta (OI) is genetically heterogeneous. Mutations in COL1A1 and COL1A2 are responsible for at least 90% of the cases, which are transmitted in an autosomal dominant manner or are de novo events. We identified a Thai boy with OI whose parents were first cousins. Because the proband was the product of a consanguineous marriage, we hypothesized that he might be homozygous for a mutation in a known gene causing a recessive form of OI. Using whole exome sequencing (WES), we did not find any pathogenic mutations in any known gene responsible for an autosomal recessive form of OI. Instead, we identified a COL1A1 frameshift mutation, c.1290delG (p.Gly431Valfs*110) in heterozygosis. By Sanger sequencing, the mutation was confirmed in the proband, and not detected in his parents, indicating that it was a de novo mutation. These findings had implication for genetic counseling. In conclusion, we expanded the mutational spectrum of COL1A1 and provided another example of a de novo pathogenic mutation in heterozygosis in a patient born to consanguineous parents.

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