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1.
Med Sci Monit ; 26: e921611, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32218412

RESUMO

BACKGROUND Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, but its etiology is unclear. Multiple genetic mutations have been reported to be associated with AIS. MATERIAL AND METHODS We enrolled a cohort of 113 surgically treated AIS patients with available parental subjects from the Peking Union Medical College Hospital. We performed whole-exome sequencing in 10 trio families and whole-genome sequencing in 103 singleton patients. Luciferase assay was used to detect the functional alterations of candidate ESR1 and ESR2 variants. RESULTS Using a de novo strategy, a missense variant in ESR1 (c.868A>G) was selected as a candidate gene for AIS. The main Cobb angle of this patient was 41° (T6-T10). Another potential pathogenic variant in ESR2 (c.236T>C) was identified. The main curve of the patient was 45° at T10-L3. The transactivation capacities of the mutated ESR1 and ESR2 protein were both significantly decreased (p=0.026 and 0.014, respectively). CONCLUSIONS Potential pathogenic variants in ESR1 and ESR2 were identified in 113 AIS patients, suggesting that genetic mutations in ESR1/2 were associated with the risk of AIS.

2.
Mol Genet Genomic Med ; 8(1): e1023, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31774634

RESUMO

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro. CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

3.
J Neurointerv Surg ; 12(2): 221-226, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31401562

RESUMO

BACKGROUND: Genetic risk factors play an important role in the pathogenesis of familial intracranial aneurysms (FIAs); however, the molecular mechanisms remain largely unknown. OBJECTIVE: To investigate potential FIA-causing genetic variants by rare variant interrogation and a family-based genomics approach in a large family with an extensive multigenerational pedigree with FIAs. METHOD: Exome sequencing (ES) was performed in a dominant likely family with intracranial aneurysms (IAs). Variants were analyzed by an in-house developed pipeline and prioritized using various filtering strategies, including population frequency, variant type, and predicted variant pathogenicity. Sanger sequencing was also performed to evaluate the segregation of the variants with the phenotype. RESULTS: Based on the ES data obtained from five individuals from a family with 7/21 living members affected with IAs, a total of 14 variants were prioritized as candidate variants. Familial segregation analysis revealed that NFX1 c.2519T>C (p.Leu840Pro) segregated in accordance with Mendelian expectations with the phenotype within the family-that is, present in all IA-affected cases and absent from all unaffected members of the second generation. This missense variant is absent from public databases (1000genome, ExAC, gnomAD, ESP5400), and has damaging predictions by bioinformatics tools (Gerp ++ score = 5.88, CADD score = 16.43, MutationTaster score = 1, LRT score = 0). In addition, 840Leu in NFX1 is robustly conserved in mammals and maps in a region before the RING-type zinc finger domain. CONCLUSION: NFX1 c.2519T>C (p.Leu840Pro) may contribute to the pathogenetics of a subset of FIAs.

4.
Hum Mutat ; 41(1): 182-195, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31471994

RESUMO

Congenital scoliosis (CS) is a birth defect with variable clinical and anatomical manifestations due to spinal malformation. The genetic etiology underlying about 10% of CS cases in the Chinese population is compound inheritance by which the gene dosage is reduced below that of haploinsufficiency. In this genetic model, the trait manifests as a result of the combined effect of a rare variant and common pathogenic variant allele at a locus. From exome sequencing (ES) data of 523 patients in Asia and two patients in Texas, we identified six TBX6 gene-disruptive variants from 11 unrelated CS patients via ES and in vitro functional testing. The in trans mild hypomorphic allele was identified in 10 of the 11 subjects; as anticipated these 10 shared a similar spinal deformity of hemivertebrae. The remaining case has a homozygous variant in TBX6 (c.418C>T) and presents a more severe spinal deformity phenotype. We found decreased transcriptional activity and abnormal cellular localization as the molecular mechanisms for TBX6 missense loss-of-function alleles. Expanding the mutational spectrum of TBX6 pathogenic alleles enabled an increased molecular diagnostic detection rate, provided further evidence for the gene dosage-dependent genetic model underlying CS, and refined clinical classification.

5.
J Hum Genet ; 65(3): 221-230, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31827250

RESUMO

Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher's exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-ß) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS.

6.
Curr Gene Ther ; 19(4): 242-247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31549955

RESUMO

OBJECTIVE: The genetic variations contributed to a substantial proportion of congenital vertebral malformations (CVM). SOX9 gene, a member of the SOX gene family, has been implicated in CVM. To study the SOX9 mutation in CVM patients is of great significance to explain the pathogenesis of scoliosis (the clinical manifestation of CVM) and to explore the pathogenesis of SOX9-related skeletal deformities. METHODS: A total of 50 singleton patients with CVM were included in this study. Exome Sequencing (ES) was performed on all the patients. The recurrent candidate variant of SOX9 gene was validated by Sanger sequencing. Luciferase assay was performed to investigate the functional changes of this variant. RESULTS: A recurrent rare heterozygous missense variant in SOX9 gene (NM_000346.3: c.1405A>G, p.M469V) which had not been reported previously was identified in three CVM patients who had the clinical findings of congenital scoliosis without deformities in other systems. This variant was absent from our in-house database and it was predicted to be deleterious (CADD = 24.5). The luciferase assay demonstrated that transactivation capacity of the mutated SOX9 protein was significantly lower than that of the wild-type for the two luciferase reporters (p = 0.0202, p = 0.0082, respectively). CONCLUSION: This SOX9 mutation (p.M469V) may contribute to CVM without other systematic deformity, which provides important implications and better understanding of phenotypic variability in SOX9-related skeletal deformities.

7.
Genet Med ; 21(7): 1548-1558, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30636772

RESUMO

PURPOSE: To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model. METHODS: Patients with congenital scoliosis (CS) from China(N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes. A mouse model for Tbx6 compound inheritance (N = 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition of TBX6-associated CS (TACS). RESULTS: In cohort 1, TACS patients (N = 33) were significantly younger at onset than the remaining CS patients (P = 0.02), presented with one or more hemivertebrae/butterfly vertebrae (P = 4.9 × 10‒8), and exhibited vertebral malformations involving the lower part of the spine (T8-S5, P = 4.4 × 10‒3); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 × 10‒7), while intraspinal anomalies were uncommon (P = 7.0 × 10‒7). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 × 10‒15). A Tbx6-/mh (mild-hypomorphic) mouse model supported that a gene dosage effect underlies the TACS phenotype. CONCLUSION: TACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10% of CS.


Assuntos
Dosagem de Genes , Padrões de Herança , Escoliose/congênito , Escoliose/genética , Proteínas com Domínio T/genética , Animais , Estudos de Coortes , Modelos Animais de Doenças , Humanos , Camundongos , Modelos Genéticos , Escoliose/classificação , Escoliose/patologia , Coluna Vertebral/patologia
8.
J Hum Genet ; 63(11): 1119-1128, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30115950

RESUMO

Intracranial vertebral-basilar artery dissection (IVAD) is an arterial disorder leading to life-threatening consequences. Genetic factors are known to be causative to certain syndromic forms of IVAD. However, systematic study of the molecular basis of sporadic and isolated IVAD is lacking. To identify genetic variants contributing to the etiology of IVAD, we enrolled a cohort of 44 unrelated cases with a clinical diagnosis of isolated IVAD and performed whole-exome sequencing (WES) for all the participants; a trio exome sequencing approach was used when samples from both parents were available. Four previously reported disease-causing heterozygous variants (three in COL3A1 and one in FBN1) and seven novel heterozygous variants in IVAD-related genes were identified. In addition, six variants in novel IVAD genes including two de novo heterozygous nonsynonymous variants (each in VPS52 and CDK18), two stop-gain variants (each in MYH9 and LYL1), and two heterozygous biallelic variants in TNXB were considered to be possibly contributing to the phenotype, with unknown significance according to the existing knowledge. A significantly higher mutational rate of IVAD candidate genes was observed in patients versus our in-house controls (P = 0.002) (DISCO study, http://www.discostudy.org/ , n = 2248). Our study provided a mutational landscape for patients with isolated IVAD.


Assuntos
Aneurisma Dissecante/genética , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Aneurisma Intracraniano/genética , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Estudos de Coortes , Colágeno Tipo III/genética , Feminino , Fibrilina-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Motores Moleculares/genética , Cadeias Pesadas de Miosina/genética , Proteínas de Neoplasias/genética
9.
J Med Genet ; 55(10): 675-684, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30120215

RESUMO

BACKGROUND: Brain arteriovenous malformations (BAVM) represent a congenital anomaly of the cerebral vessels with a prevalence of 10-18/100 000. BAVM is the leading aetiology of intracranial haemorrhage in children. Our objective was to identify gene variants potentially contributing to disease and to better define the molecular aetiology underlying non-syndromic sporadic BAVM. METHODS: We performed whole-exome trio sequencing of 100 unrelated families with a clinically uniform BAVM phenotype. Pathogenic variants were then studied in vivo using a transgenic zebrafish model. RESULTS: We identified four pathogenic heterozygous variants in four patients, including one in the established BAVM-related gene, ENG, and three damaging variants in novel candidate genes: PITPNM3, SARS and LEMD3, which we then functionally validated in zebrafish. In addition, eight likely pathogenic heterozygous variants (TIMP3, SCUBE2, MAP4K4, CDH2, IL17RD, PREX2, ZFYVE16 and EGFR) were identified in eight patients, and 16 patients carried one or more variants of uncertain significance. Potential oligogenic inheritance (MAP4K4 with ENG, RASA1 with TIMP3 and SCUBE2 with ENG) was identified in three patients. Regulation of sma- and mad-related proteins (SMADs) (involved in bone morphogenic protein (BMP)/transforming growth factor beta (TGF-ß) signalling) and vascular endothelial growth factor (VEGF)/vascular endotheliual growth factor recepter 2 (VEGFR2) binding and activity (affecting the VEGF signalling pathway) were the most significantly affected biological process involved in the pathogenesis of BAVM. CONCLUSIONS: Our study highlights the specific role of BMP/TGF-ß and VEGF/VEGFR signalling in the aetiology of BAVM and the efficiency of intensive parallel sequencing in the challenging context of genetically heterogeneous paradigm.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Variação Genética , Malformações Arteriovenosas Intracranianas/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Fator de Crescimento Transformador beta/genética , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Animais Geneticamente Modificados , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , China , Estudos de Coortes , Modelos Animais de Doenças , Família , Feminino , Heterozigoto , Humanos , Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/patologia , Masculino , Transdução de Sinais , Sequenciamento Completo do Exoma , Peixe-Zebra
10.
Hum Genet ; 137(6-7): 553-567, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30019117

RESUMO

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be 'induced' by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p < 1 × 10-6 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.


Assuntos
Anormalidades Congênitas/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Escoliose/genética , Adolescente , Anormalidades Congênitas/fisiopatologia , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Haplótipos/genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Escoliose/fisiopatologia
11.
Guang Pu Xue Yu Guang Pu Fen Xi ; 34(10): 2851-7, 2014 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-25739237

RESUMO

In order to provide the experiences and references to the researchers who are working on infrared (IR) mixed gas detection field. The proposed manuscript reviews two sections of the aforementioned field, including optical multiplexing structure and detection method. At present, the coherent light sources whose representative are quantum cascade laser (QCL) and inter-band cascade laser(ICL) become the mainstream light source in IR mixed gas detection, which replace the traditional non-coherent light source, such as IR radiation source and IR light emitting diode. In addition, the photon detector which has a super high detectivity and very short response time is gradually beyond thermal infrared detector, dominant in the field of infrared detector. The optical multiplexing structure is the key factor of IR mixed gas detection system, which consists of single light source multi-plexing detection structure and multi light source multiplexing detection structure. Particularly, single light source multiplexing detection structure is advantages of small volume and high integration, which make it a plausible candidate for the portable mixed gas detection system; Meanwhile, multi light source multiplexing detection structure is embodiment of time division multiplex, frequency division multiplexing and wavelength division multiplexing, and become the leading structure of the mixed gas detection system because of its wider spectral range, higher spectral resolution, etc. The detection method applied to IR mixed gas detection includes non-dispersive infrared (NDIR) spectroscopy, wavelength and frequency-modulation spectroscopy, cavity-enhanced spectroscopy and photoacoustic spectroscopy, etc. The IR mixed gas detection system designed by researchers after recognizing the whole sections of the proposed system, which play a significant role in industrial and agricultural production, environmental monitoring, and life science, etc.

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