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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(3): 294-299, 2024 Mar 10.
Artículo en Zh | MEDLINE | ID: mdl-38448017

RESUMEN

OBJECTIVE: To explore the clinical application of preimplantation genetic testing for monogenic disorders (PGT-M) in an unique case with Spinal muscular atrophy (SMA) type 2+0. METHODS: A special SMA family presented at the Third Affiliated Hospital of Guangzhou Medical University on October 19, 2020 was selected as the study subject. Multiple ligation-dependent probe amplification (MLPA) and molecular tagging linkage analysis were carried out to identify the SMN1 genotype of the couple and their fetus. Subsequently, next-generation sequencing (NGS), molecular tagging linkage analysis, and chromosomal microarray analysis were employed to determine the haplotypes and validate the result of PGT-M on the 11 embryos derived for the couple. RESULTS: The female partner was identified as a carrier of the rare SMN1[2+0] variant, and prenatal diagnosis confirmed the fetus to be affected by SMA. Ultimately, PGT-M has successfully selected four embryos free from the pathogenic SMN1 variants and X chromosome deletion. CONCLUSION: PGT-M can effectively prevent the transmission of rare genetic variants such as the SMA 2+0 subtype in the families. Above finding has provided guidance for genetic counseling and family planning for the couple.


Asunto(s)
Pruebas Genéticas , Atrofia Muscular Espinal , Embarazo , Femenino , Humanos , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Genotipo , Asesoramiento Genético , Haplotipos
2.
Hum Reprod ; 37(11): 2546-2559, 2022 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-36066440

RESUMEN

STUDY QUESTION: Is there an efficient and cost-effective detection platform for different genetic conditions about embryos? SUMMARY ANSWER: A multifunctional haplotyping-based preimplantation genetic testing platform was provided for detecting different genetic conditions. WHAT IS KNOWN ALREADY: Genetic disease and chromosomal rearrangement have been known to significantly impact fertility and development. Therefore, preimplantation genetic testing for aneuploidy (PGT-A), monogenic disorders (PGT-M) and structural rearrangements (PGT-SR), a part of ART, has been presented together to minimize the fetal genetic risk and increase pregnancy rate. For patients or their families who are suffering from chromosome abnormality, monogenic disease, unexplained repeated spontaneous abortion or implantation failure, after accepting genetic counseling, they may be suggested to accept detection from more than one PGT platforms about the embryos to avoid some genetic diseases. However, PGT platforms work through different workflows. The high costliness, lack of material and long-time operation of combined PGT platforms limit their application. STUDY DESIGN, SIZE, DURATION: All 188 embryonic samples from 43 families were tested with HaploPGT platform, and most of their genetic abnormalities had been determined by different conventional PGT methods beforehand. Among them, there were 12 families only carrying structural rearrangements (115 embryos) in which 9 families accepted implantation and 5 families had normal labor ART outcomes, 7 families only carrying monogenic diseases (26 embryos) and 3 families carrying both structural rearrangements and monogenic diseases (26 embryos). Twelve monopronucleated zygotes (1PN) samples and 9 suspected triploid samples were collected from 21 families. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Here, we raised a comprehensive PGT method called HaploPGT, combining reduced representation genome sequencing, read-count analysis, B allele frequency and haplotyping analysis, to simultaneously detect different genetic disorders in one single test. MAIN RESULTS AND THE ROLE OF CHANCE: With 80 million reads (80M) genomic data, the proportion of windows (1 million base pairs (Mb)) containing two or more informative single nucleotide polymorphism (SNP) sites was 97.81%, meanwhile the genotyping error rate stabilized at a low level (2.19%). Furthermore, the informative SNPs were equally distributed across the genome, and whole-genomic haplotyping was established. Therefore, 80M was chosen to balance the cost and accuracy in HaploPGT. HaploPGT was able to identify abnormal embryos with triploid, global and partial loss of heterozygosity, and even to distinguish parental origin of copy number variation in mosaic and non-mosaic embryos. Besides, by retrospectively analyzing 188 embryonic samples from 43 families, HaploPGT revealed 100% concordance with the available results obtained from reference methods, including PGT-A, PGT-M, PGT-SR and PGT-HLA. LIMITATIONS, REASON FOR CAUTION: Despite the numerous benefits HaploPGT could bring, it still required additional family members to deduce the parental haplotype for identifying balanced translocation and monogenic mutation in tested embryos. In terms of PGT-SR, the additional family member could be a reference embryo with unbalanced translocation. For PGT-M, a proband was normally required. In both cases, genomic information from grandparents or parental siblings might help for haplotyping theoretically. Another restriction was that haploid, and diploid resulting from the duplication of a haploid, could not be told apart by HaploPGT, but it was able to recognize partial loss of heterozygosity in the embryonic genome. In addition, it should be noted that the location of rearrangement breakpoints and the situation of mutation sites were complicated, which meant that partial genetic disorders might not be completely detected. WIDER IMPLICATIONS OF THE FINDINGS: HaploPGT is an efficient and cost-effective detection platform with high clinical value for detecting genetic status. This platform could promote the application of PGT in ART, to increase pregnancy rate and decrease the birth of children with genetic diseases. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the National Natural Science Foundation of China (81873478, to L.H.), National Key R&D Program of China (2018YFC1003100, to L.H.), the Natural Science Foundation of Hunan Province (Grant 2022JJ30414, to P.X.), Hunan Provincial Grant for Innovative Province Construction (2019SK4012) and the Scientific Research Foundation of Reproductive and Genetic Hospital of China International Trust & Investment Corporation (CITIC)-Xiangya (YNXM-201910). Haplotyping analysis has been licensed to Basecare Co., Ltd. L.K., Y.M., K.K., D.Z., N.L., J.Z. and R.D. are Basecare Co., Ltd employees. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.


Asunto(s)
Diagnóstico Preimplantación , Embarazo , Femenino , Niño , Humanos , Diagnóstico Preimplantación/métodos , Haplotipos , Estudios Retrospectivos , Triploidía , Variaciones en el Número de Copia de ADN , Pruebas Genéticas/métodos , Aneuploidia , Aberraciones Cromosómicas
3.
J Med Genet ; 58(1): 41-47, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32381727

RESUMEN

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.


Asunto(s)
Predisposición Genética a la Enfermedad , Escoliosis/diagnóstico , Escoliosis/genética , Adolescente , Adulto , Edad de Inicio , Preescolar , China/epidemiología , Estudios de Cohortes , Exoma/genética , Femenino , Humanos , Masculino , Estudios Retrospectivos , Escoliosis/clasificación , Escoliosis/patología , Secuenciación del Exoma
4.
Genome Res ; 28(8): 1228-1242, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29907612

RESUMEN

Alu elements, the short interspersed element numbering more than 1 million copies per human genome, can mediate the formation of copy number variants (CNVs) between substrate pairs. These Alu/Alu-mediated rearrangements (AAMRs) can result in pathogenic variants that cause diseases. To investigate the impact of AAMR on gene variation and human health, we first characterized Alus that are involved in mediating CNVs (CNV-Alus) and observed that these Alus tend to be evolutionarily younger. We then computationally generated, with the assistance of a supercomputer, a test data set consisting of 78 million Alu pairs and predicted ∼18% of them are potentially susceptible to AAMR. We further determined the relative risk of AAMR in 12,074 OMIM genes using the count of predicted CNV-Alu pairs and experimentally validated the predictions with 89 samples selected by correlating predicted hotspots with a database of CNVs identified by clinical chromosomal microarrays (CMAs) on the genomes of approximately 54,000 subjects. We fine-mapped 47 duplications, 40 deletions, and two complex rearrangements and examined a total of 52 breakpoint junctions of simple CNVs. Overall, 94% of the candidate breakpoints were at least partially Alu mediated. We successfully predicted all (100%) of Alu pairs that mediated deletions (n = 21) and achieved an 87% positive predictive value overall when including AAMR-generated deletions and duplications. We provided a tool, AluAluCNVpredictor, for assessing AAMR hotspots and their role in human disease. These results demonstrate the utility of our predictive model and provide insights into the genomic features and molecular mechanisms underlying AAMR.


Asunto(s)
Elementos Alu/genética , Variaciones en el Número de Copia de ADN/genética , Inestabilidad Genómica/genética , Duplicación de Gen/genética , Genoma Humano/genética , Humanos , Eliminación de Secuencia
5.
J Med Genet ; 57(6): 371-379, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31888956

RESUMEN

BACKGROUND: Congenital vertebral malformations (CVMs) manifest with abnormal vertebral morphology. Genetic factors have been implicated in CVM pathogenesis, but the underlying pathogenic mechanisms remain unclear in most subjects. We previously reported that the human 16p11.2 BP4-BP5 deletion and its associated TBX6 dosage reduction caused CVMs. We aim to investigate the reciprocal 16p11.2 BP4-BP5 duplication and its potential genetic contributions to CVMs. METHODS AND RESULTS: Patients who were found to carry the 16p11.2 BP4-BP5 duplication by chromosomal microarray analysis were retrospectively analysed for their vertebral phenotypes. The spinal assessments in seven duplication carriers showed that four (57%) presented characteristics of CVMs, supporting the contention that increased TBX6 dosage could induce CVMs. For further in vivo functional investigation in a model organism, we conducted genome editing of the upstream regulatory region of mouse Tbx6 using CRISPR-Cas9 and obtained three mouse mutant alleles (Tbx6up1 to Tbx6up3 ) with elevated expression levels of Tbx6. Luciferase reporter assays showed that the Tbx6up3 allele presented with the 160% expression level of that observed in the reference (+) allele. Therefore, the homozygous Tbx6up3/up3 mice could functionally mimic the TBX6 dosage of heterozygous carriers of 16p11.2 BP4-BP5 duplication (approximately 150%, ie, 3/2 gene dosage of the normal level). Remarkably, 60% of the Tbx6up3/up3 mice manifested with CVMs. Consistent with our observations in humans, the CVMs induced by increased Tbx6 dosage in mice mainly affected the cervical vertebrae. CONCLUSION: Our findings in humans and mice consistently support that an increased TBX6 dosage contributes to the risk of developing cervical CVMs.


Asunto(s)
Vértebras Cervicales/anomalías , Escoliosis/genética , Proteínas de Dominio T Box/genética , Alelos , Animales , Vértebras Cervicales/patología , Modelos Animales de Enfermedad , Dosificación de Gen/genética , Genotipo , Heterocigoto , Humanos , Ratones , Mutación/genética , Fenotipo , Escoliosis/diagnóstico por imagen , Escoliosis/patología
6.
Hum Mutat ; 41(1): 182-195, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31471994

RESUMEN

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.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Patrón de Herencia , Mutación Missense , Proteínas de Dominio T Box/genética , Alelos , Línea Celular , Femenino , Expresión Génica , Genes Reporteros , Genotipo , Haplotipos , Humanos , Masculino , Modelos Moleculares , Técnicas de Diagnóstico Molecular , Fenotipo , Conformación Proteica , Radiografía , Análisis de Secuencia de ADN , Columna Vertebral/anomalías , Columna Vertebral/diagnóstico por imagen , Relación Estructura-Actividad , Proteínas de Dominio T Box/química , Secuenciación del Exoma
7.
Kidney Int ; 98(4): 1020-1030, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32450157

RESUMEN

Congenital anomalies of the kidney and urinary tract (CAKUTs) are the most common cause of chronic kidney disease in children. Human 16p11.2 deletions have been associated with CAKUT, but the responsible molecular mechanism remains to be illuminated. To explore this, we investigated 102 carriers of 16p11.2 deletion from multi-center cohorts, among which we retrospectively ascertained kidney morphologic and functional data from 37 individuals (12 Chinese and 25 Caucasian/Hispanic). Significantly higher CAKUT rates were observed in 16p11.2 deletion carriers (about 25% in Chinese and 16% in Caucasian/Hispanic) than those found in the non-clinically ascertained general populations (about 1/1000 found at autopsy). Furthermore, we identified seven additional individuals with heterozygous loss-of-function variants in TBX6, a gene that maps to the 16p11.2 region. Four of these seven cases showed obvious CAKUT. To further investigate the role of TBX6 in kidney development, we engineered mice with mutated Tbx6 alleles. The Tbx6 heterozygous null (i.e., loss-of-function) mutant (Tbx6+/‒) resulted in 13% solitary kidneys. Remarkably, this incidence increased to 29% in a compound heterozygous model (Tbx6mh/‒) that reduced Tbx6 gene dosage to below haploinsufficiency, by combining the null allele with a novel mild hypomorphic allele (mh). Renal hypoplasia was also frequently observed in these Tbx6-mutated mouse models. Thus, our findings in patients and mice establish TBX6 as a novel gene involved in CAKUT and its gene dosage insufficiency as a potential driver for kidney defects observed in the 16p11.2 microdeletion syndrome.


Asunto(s)
Escoliosis , Animales , Humanos , Riñón , Ratones , Estudios Retrospectivos , Proteínas de Dominio T Box/genética , Anomalías Urogenitales , Reflujo Vesicoureteral
8.
Genet Med ; 21(7): 1548-1558, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30636772

RESUMEN

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.


Asunto(s)
Dosificación de Gen , Patrón de Herencia , Escoliosis/congénito , Escoliosis/genética , Proteínas de Dominio T Box/genética , Animales , Estudios de Cohortes , Modelos Animales de Enfermedad , Humanos , Ratones , Modelos Genéticos , Escoliosis/clasificación , Escoliosis/patología , Columna Vertebral/patología
9.
J Med Genet ; 55(10): 675-684, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30120215

RESUMEN

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.


Asunto(s)
Proteínas Morfogenéticas Óseas/genética , Variación Genética , Malformaciones Arteriovenosas Intracraneales/genética , Receptores de Factores de Crecimiento Endotelial Vascular/genética , Factor de Crecimiento Transformador beta/genética , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Animales Modificados Genéticamente , Encéfalo/diagnóstico por imagen , Encéfalo/patología , China , Estudios de Cohortes , Modelos Animales de Enfermedad , Familia , Femenino , Heterocigoto , Humanos , Malformaciones Arteriovenosas Intracraneales/diagnóstico por imagen , Malformaciones Arteriovenosas Intracraneales/patología , Masculino , Transducción de Señal , Secuenciación del Exoma , Pez Cebra
10.
Hum Genet ; 137(9): 689-703, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30046887

RESUMEN

Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM #150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM #614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM #104530; Epidermolysis bullosa, junctional, MIMs #226700 and #226650), and BCOR (Microphthalmia, syndromic 2, MIM #300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype-phenotype relationship in the common complex trait of TA.


Asunto(s)
Anodoncia/genética , Moléculas de Adhesión Celular/genética , Marcadores Genéticos , Mutación , Proteínas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Proteínas Wnt/genética , Anodoncia/epidemiología , Anodoncia/patología , Niño , Preescolar , Femenino , Humanos , Masculino , Linaje , Fenotipo , Turquía/epidemiología , Kalinina
11.
Hum Genet ; 137(6-7): 553-567, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30019117

RESUMEN

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.


Asunto(s)
Anomalías Congénitas/genética , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad , Escoliosis/genética , Adolescente , Anomalías Congénitas/fisiopatología , Femenino , Genoma Humano/genética , Estudio de Asociación del Genoma Completo , Genómica , Genotipo , Haplotipos/genética , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Escoliosis/fisiopatología
12.
J Hum Genet ; 63(11): 1119-1128, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30115950

RESUMEN

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.


Asunto(s)
Disección Aórtica/genética , Exoma , Secuenciación de Nucleótidos de Alto Rendimiento , Aneurisma Intracraneal/genética , Adulto , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Estudios de Cohortes , Colágeno Tipo III/genética , Femenino , Fibrilina-1/genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas Motoras Moleculares/genética , Cadenas Pesadas de Miosina/genética , Proteínas de Neoplasias/genética
13.
Am J Med Genet A ; 176(4): 1015-1022, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29436111

RESUMEN

Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.


Asunto(s)
Alelos , Anodoncia/diagnóstico , Anodoncia/genética , Estudios de Asociación Genética , Mutación , Proteínas de Neoplasias/genética , Fenotipo , Receptores de Superficie Celular/genética , Sustitución de Aminoácidos , Animales , Niño , Consanguinidad , Facies , Genotipo , Humanos , Masculino , Ratones , Proteínas de Microfilamentos , Linaje , Radiografía , Secuenciación del Exoma
14.
Hum Mol Genet ; 24(5): 1225-33, 2015 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-25324539

RESUMEN

Non-allelic homologous recombination (NAHR) is one of the key mechanisms of DNA rearrangement. NAHR occurring between direct homologous repeats can generate genomic copy number variation (CNV) and make significant contributions to both genome evolution and human diseases such as cancer. Intriguingly, previous observations on the rare CNVs at certain genomic disorder loci suggested that NAHR frequency could be dependent on homology properties. However, such a correlation remains unclear at the other NAHR-mediated CNV loci, especially the common CNVs in human populations. Different from the rare CNVs associated with genomic disorders, it is challenging to identify de novo NAHR events at common CNV loci. Therefore, our previously proposed statistic M was employed in estimating relative mutation rate for the NAHR-mediated CNVs in human populations. By utilizing generalized regression neural network and principal component analysis in studying 4330 CNVs ascertained in 3 HapMap populations, we identified the CNVs mediated by NAHR between paired segmental duplications (SDs) and further revealed the correlations between SD properties and NAHR probability. SD length and inter-SD distance were shown to make major contributions to the occurrence of NAHR, whereas chromosomal position and sequence similarity of paired SDs are also involved in NAHR. An integrated effect of SD properties on NAHR frequency was revealed for the common CNVs in human populations. These observations can be well explained by ectopic synapsis in NAHR together with our proposed model of chromosomal compression/extension/looping (CCEL) for homology mis-pairing. Our findings showed the important roles of SDs in NAHR and human genomic evolution.


Asunto(s)
Variaciones en el Número de Copia de ADN , Genoma Humano , Recombinación Homóloga , Alelos , Cromosomas Humanos/genética , Cromosomas Humanos/metabolismo , Evolución Molecular , Reordenamiento Génico , Sitios Genéticos , Genómica , Humanos , Modelos Teóricos , Tasa de Mutación , Análisis de Componente Principal , Secuencias Repetitivas de Ácidos Nucleicos , Duplicaciones Segmentarias en el Genoma , Alineación de Secuencia
15.
J Hum Genet ; 61(11): 917-922, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27383657

RESUMEN

The ossicles represent one of the most fundamental morphological features in evolutionary biology of the mammalians. The mobile ossicular morphology abnormalities result in the severe conductive hearing loss. Development and patterning of the middle ear malformation depend on genetic and environmental causes. However, the genetic basis for the risk of congenital ossicle malformation is poorly understood. We show here nine affected individuals in a Chinese pedigree who had bilateral conductive hearing loss with ptosis. We performed whole-genome sequencing and array comparative genomic hybridization (CGH) analysis on DNA samples from the Chinese pedigree. We confirmed the presence of a novel 60 kb heterozygous deletion in size, encompassing SIX2 in our family. Mutation screening in 169 sporadic cases with external ear and middle ear malformations identified no pathogenic variant or polymorphism. We suggest SIX2 haploinsufficiency as a potential congenital factor could be attributed to developmental malformation of the middle ear ossicles and upper eyelid. To the best of our knowledge, this is the first report to provide a description of copy number variation in the SIX2 gene resulting in syndromic conductive hearing loss.


Asunto(s)
Estudios de Asociación Genética , Haploinsuficiencia , Pérdida Auditiva Conductiva/diagnóstico , Pérdida Auditiva Conductiva/genética , Proteínas de Homeodominio/genética , Proteínas del Tejido Nervioso/genética , Fenotipo , Audiometría , Biopsia , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Masculino , Mutación , Linaje , Radiografía , Tomografía Computarizada Espiral
16.
BMC Bioinformatics ; 15: 50, 2014 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-24555668

RESUMEN

BACKGROUND: Copy Number Variations (CNVs) are usually inferred from Single Nucleotide Polymorphism (SNP) arrays by use of some software packages based on given algorithms. However, there is no clear understanding of the performance of these software packages; it is therefore difficult to select one or several software packages for CNV detection based on the SNP array platform.We selected four publicly available software packages designed for CNV calling from an Affymetrix SNP array, including Birdsuite, dChip, Genotyping Console (GTC) and PennCNV. The publicly available dataset generated by Array-based Comparative Genomic Hybridization (CGH), with a resolution of 24 million probes per sample, was considered to be the "gold standard". Compared with the CGH-based dataset, the success rate, average stability rate, sensitivity, consistence and reproducibility of these four software packages were assessed compared with the "gold standard". Specially, we also compared the efficiency of detecting CNVs simultaneously by two, three and all of the software packages with that by a single software package. RESULTS: Simply from the quantity of the detected CNVs, Birdsuite detected the most while GTC detected the least. We found that Birdsuite and dChip had obvious detecting bias. And GTC seemed to be inferior because of the least amount of CNVs it detected. Thereafter we investigated the detection consistency produced by one certain software package and the rest three software suits. We found that the consistency of dChip was the lowest while GTC was the highest. Compared with the CNVs detecting result of CGH, in the matching group, GTC called the most matching CNVs, PennCNV-Affy ranked second. In the non-overlapping group, GTC called the least CNVs. With regards to the reproducibility of CNV calling, larger CNVs were usually replicated better. PennCNV-Affy shows the best consistency while Birdsuite shows the poorest. CONCLUSION: We found that PennCNV outperformed the other three packages in the sensitivity and specificity of CNV calling. Obviously, each calling method had its own limitations and advantages for different data analysis. Therefore, the optimized calling methods might be identified using multiple algorithms to evaluate the concordance and discordance of SNP array-based CNV calling.


Asunto(s)
Hibridación Genómica Comparativa/métodos , Variaciones en el Número de Copia de ADN/genética , Polimorfismo de Nucleótido Simple/genética , Programas Informáticos , Algoritmos , Biología Computacional/métodos , Genoma Humano/genética , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
17.
Genes Genomics ; 45(4): 531-542, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36115009

RESUMEN

BACKGROUND: Infertility is a common and rapidly growing health issue around the world. The genetic analysis based on the infertile population is crucial for intervention and treatment. OBJECTIVE: To find candidate gene locus led to azoospermia in Chinese multi-ethnic groups and provide theoretical guidance for the diagnosis of genetic diseases to progressively aggravated infertility patients and sterile offspring with ART. METHODS: The study based on whole-exome sequencing (WES) was presented for genetic characteristic analysis of multi-ethnics and identification of variants related to infertility in Xinjiang area of China. RESULTS: The frequency of pathogenic variants showed significant ethnic differences among four main ethnics in Xinjiang. The population structure analysis confirmed that the Hui was close to the Han population, the Kazak was close to the Uygur population, and there are three ancestry components in the four ethnics. In addition, ten candidate variants potentially regulated azoospermia were detected, and KNTC1 (rs7968222: G > T) was chosen to validate the association. Through the analysis in the valid group, the frequency of rs7968222 (G > T) has a significant difference in the azoospermia population (11.76%, 8/68) and normospermia population (4.63%, 35/756) (P < 0.001). Interestingly, the proportion of people with abnormal follicle-stimulating hormone (FSH) level in the group carrying rs7968222 (G > T) was significantly higher than non-carriers (P < 0.05). Therefore, rs7968222 may regulate spermatogenesis through affecting hormone level. CONCLUSION: Our study establishes the genetics analysis of Northwest China and finds a candidate gene locus KNTC1 (rs7968222: G > T), which is one of the genetic susceptibility factors for male azoospermia.


Asunto(s)
Azoospermia , Proteínas de Ciclo Celular , Proteínas Asociadas a Microtúbulos , Humanos , Masculino , Azoospermia/genética , Pueblos del Este de Asia , Etnicidad/genética , Secuenciación del Exoma , Predisposición Genética a la Enfermedad/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Ciclo Celular/genética
18.
Hum Genet ; 131(7): 1217-24, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22367439

RESUMEN

While pathogenic copy number variations (CNVs) in 15q11.2 were recently identified in Caucasian patients with idiopathic generalized epilepsies (IGEs), the epilepsy-associated gene(s) in this region is/are still unknown. Our study investigated whether the CNVs in 15q11.2 are associated with childhood absence epilepsy (CAE) in Chinese patients and whether the selective magnesium transporter NIPA2 gene affected by 15q11.2 microdeletions is a susceptive gene for CAE. We assessed IGE-related CNVs by Affymetrix SNP 5.0 microarrays in 198 patients with CAE and 198 controls from northern China, and verified the identified CNVs by high-density oligonucleotide-based CGH microarrays. The coding region and exon-intron boundaries of NIPA2 were sequenced in all 380 patients with CAE and 400 controls. 15q11.2 microdeletions were detected in 3 of 198 (1.5%) patients and in no controls. Furthermore, we identified point mutations or indel in a heterozygous state of the NIPA2 gene in 3 out of 380 patients, whereas they were absent in 700 controls (P = 0.043). These mutations included two novel missense mutations (c.532A>T, p.I178F; c.731A>G, p.N244S) and one small novel insertion (c.1002_1003insGAT, p.N334_335EinsD). No NIPA2 mutation was found in 400 normal controls. We first identified that NIPA2, encoding a selective magnesium transporter, is a susceptible gene of CAE, and 15q11.2 microdeletions are important pathogenic CNVs for CAE with higher frequency in Chinese populations than that previously reported in Caucasians. The haploinsufficiency of NIPA2 may be a mechanism underlying the neurological phenotypes of 15q11.2 microdeletions.


Asunto(s)
Variaciones en el Número de Copia de ADN , Epilepsia Tipo Ausencia/genética , Proteínas de la Membrana/genética , Proteínas de Transporte de Catión , Niño , Aberraciones Cromosómicas , Cromosomas Humanos Par 15/genética , Femenino , Genotipo , Haploinsuficiencia , Humanos , Discapacidad Intelectual , Masculino , Mutación , Análisis de Secuencia de ADN
19.
J Hum Genet ; 57(8): 545-51, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22673690

RESUMEN

Local genomic architecture, such as segmental duplications (SDs), can induce copy number variations (CNVs) hotspots in the human genome, many of which manifest as genomic disorders. Significant technological advances have been achieved for genome-wide CNV investigations, but these costly methods are not suitable for genotyping certain disease-associated CNVs or other loci of interest in populations. Recently, two independent studies showed that the murine meiosis expressed gene 1 (Meig1) was critical to spermatogenesis. We found that the human orthologue MEIG1 is flanked by an SD pair, between which non-allelic homologous recombination (NAHR) can cause recurrent CNVs. To study this potential CNV hotspot and its role in spermatogenesis, we developed a new CNV genotyping method, AccuCopy, based on multiplex competitive amplification to investigate 320 patients with spermatogenic impairment and 93 healthy controls. Three MEIG1 duplications (two in patients and one in controls) were identified, whereas no deletion was found. As NAHR results in more recurrent deletions than duplications at a locus, the over representation of recurrent MEIG1 duplications suggests a potential purifying selection operating on this hotspot, possibly via fecundity. We also showed that AccuCopy is an efficient and reliable method for multiplex CNV genotyping.


Asunto(s)
Proteínas de Ciclo Celular/genética , Variaciones en el Número de Copia de ADN/genética , Técnicas de Genotipaje/métodos , Reacción en Cadena de la Polimerasa Multiplex/métodos , Proteínas Nucleares/genética , Fosfoproteínas/genética , Duplicaciones Segmentarias en el Genoma/genética , Animales , Genoma Humano , Recombinación Homóloga , Humanos , Infertilidad Masculina/genética , Masculino , Ratones , Homología de Secuencia de Aminoácido , Espermatozoides/patología
20.
Yi Chuan ; 33(8): 857-69, 2011 Aug.
Artículo en Zh | MEDLINE | ID: mdl-21831802

RESUMEN

Copy number variation (CNV) is the main type of structure variation (SV) caused by genomic rearrangement, which mainly includes deletion and duplication of sub-microscopic but large (>1 kb) genomic segments. CNV has been recognized as one of the main genetic factors underlying human diseases. The mutation rate (per locus) of CNV is much higher than that of single nucleotide polymorphism (SNP). The genome-wide assays for CNV study include array-based comparative genomic hybridization (aCGH), SNP genotyping microarrays, and next-generation sequencing techniques. Various molecular mechanisms are involved in CNV formation, which can be divided into two main categories, DNA recombination-based and DNA replication-based mechanisms. CNVs can be associated with Mendelian diseases, sporadic diseases, and susceptibility to complex diseases. CNVs can convey clinical phenotypes by gene dosage, gene disruption, gene fusion, and position effects. Further studies on CNVs will shed new light on human genome structure, genetic variations between individuals, and missing heritability of human diseases.


Asunto(s)
Variaciones en el Número de Copia de ADN , Enfermedad/genética , Genoma Humano , Mutación , Humanos
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