RESUMEN
BACKGROUND: Townes-Brocks syndrome (TBS) is a rare genetic disorder characterised by multiple malformations. Due to its phenotypic heterogeneity and rarity, diagnosis and recognition of TBS can be challenging and there has been a lack of investigation of patients with atypical TBS in large cohorts and delineation of their phenotypic characteristics. METHODS: We screened SALL1 and DACT1 variants using next-generation sequencing in the China Deafness Genetics Consortium (CDGC) cohort enrolling 20 666 unrelated hearing loss (HL) cases. Comprehensive clinical evaluations were conducted on seven members from a three-generation TBS family. Combining data from previously reported cases, we also provided a landscape of phenotypes and genotypes of patients with TBS. RESULTS: We identified five novel and two reported pathogenic/likely pathogenic (P/LP) SALL1 variants from seven families. Audiological features in patients differed in severity and binaural asymmetry. Moreover, previously undocumented malformations in the middle and inner ear were detected in one patient. By comprehensive clinical evaluations, we further provide evidence for the causal relationship between SALL1 variation and certain endocrine abnormalities. Penetrance analysis within familial contexts revealed incomplete penetrance among first-generation patients with TBS and a higher disease burden among their affected offspring. CONCLUSION: This study presents the first insight of genetic screening for patients with TBS in a large HL cohort. We broadened the phenotypic-genotypic spectrum of TBS and our results supported an underestimated prevalence of TBS. Due to the rarity and phenotypic heterogeneity of rare diseases, broader spectrum molecular tests, especially whole genome sequencing, can improve the situation of underdiagnosis and provide effective recommendations for clinical management.
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Anomalías Múltiples , Ano Imperforado , Pérdida Auditiva Sensorineural , Pulgar/anomalías , Factores de Transcripción , Humanos , Mutación , Factores de Transcripción/genética , Síndrome , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Fenotipo , Proteínas Nucleares/genética , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
INTRODUCTION: Women with epilepsy (WWE) are more likely to develop reproductive endocrine disorders, especially polycystic ovary syndrome (PCOS). This study aimed to explore the genetic factors of PCOS in WWE in hope of improving individual precision diagnosis and treatment. METHODS: WWE registered at West China Hospital between January 2022 and October 2022 were enrolled in this study. Demographic and epilepsy-related characteristics were recorded, and blood samples were collected for hormones, glucose metabolism testing, and whole-genome sequencing. RESULTS: After sample sequencing, quality control, and variants selection, association analyses were performed. Pathway analysis was performed to identify involved biological pathways. The overall and PCOS "burden score" of each individual were calculated to count the deleterious variants. A total of 95 WWE were included in this study and 19 patients were diagnosed with PCOS. WWE with PCOS showed a significantly different hormone profiles and a tendency of impaired glucose metabolism. The most commonly associated genes were ZFYVE28, COL19A1, SIK3, ANKK1, PPIG, and REPIN1. The top 3 canonical pathways are adipogenesis pathway, epoxysqualene biosynthesis signaling, and glutamate degradation signaling. The most significant common variant was rs11914038 located in gene CELSR1 and rs651748 located in gene ZBTB16. In human gene connectome prioritizations, ITGA9, PNPLA2, and DAB2 are the top 3 genes having the shortest distance to known PCOS genes. CONCLUSION: Genetic factors involved in the abnormal regulation of glucose and insulin metabolism are likely to be associated with the comorbidity of PCOS in WWE. Interventions targeting these processes should be given more priority in clinical practice.
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Epilepsia , Síndrome del Ovario Poliquístico , Femenino , Humanos , Síndrome del Ovario Poliquístico/epidemiología , Síndrome del Ovario Poliquístico/genética , Epilepsia/epidemiología , Epilepsia/genética , Glucosa , China , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/uso terapéutico , Proteínas Adaptadoras Transductoras de Señales/metabolismoRESUMEN
Numerous computational prediction tools have been introduced to estimate the functional impact of variants in the human genome based on evolutionary constraints and biochemical metrics. However, their implementation in diagnostic settings to classify variants faced challenges with accuracy and validity. Most existing tools are pan-genome and pan-diseases, which neglected gene- and disease-specific properties and limited the accessibility of curated data. As a proof-of-concept, we developed a disease-specific prediction tool named Deafness Variant deleteriousness Prediction tool (DVPred) that focused on the 157 genes reportedly causing genetic hearing loss (HL). DVPred applied the gradient boosting decision tree (GBDT) algorithm to the dataset consisting of expert-curated pathogenic and benign variants from a large in-house HL patient cohort and public databases. With the incorporation of variant-level and gene-level features, DVPred outperformed the existing universal tools. It boasts an area under the curve (AUC) of 0.98, and showed consistent performance (AUC = 0.985) in an independent assessment dataset. We further demonstrated that multiple gene-level metrics, including low complexity genomic regions and substitution intolerance scores, were the top features of the model. A comprehensive analysis of missense variants showed a gene-specific ratio of predicted deleterious and neutral variants, implying varied tolerance or intolerance to variation in different genes. DVPred explored the utility of disease-specific strategy in improving the deafness variant prediction tool. It can improve the prioritization of pathogenic variants among massive variants identified by high-throughput sequencing on HL genes. It also shed light on the development of variant prediction tools for other genetic disorders.
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Sordera , Pérdida Auditiva , Genómica , Pérdida Auditiva/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , VirulenciaRESUMEN
Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and overactivation of the complement alternative pathway. Typically, gene analysis for aHUS and C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-center analysis of 610 rare genetic variants in 13 mostly complement genes (CFH, CFI, CD46, C3, CFB, CFHR1, CFHR3, CFHR4, CFHR5, CFP, PLG, DGKE, and THBD) from >3500 patients with aHUS and C3G. We report 371 novel rare variants (RVs) for aHUS and 82 for C3G. Our new interactive Database of Complement Gene Variants was used to extract allele frequency data for these 13 genes using the Exome Aggregation Consortium server as the reference genome. For aHUS, significantly more protein-altering rare variation was found in five genes CFH, CFI, CD46, C3, and DGKE than in the Exome Aggregation Consortium (allele frequency < 0.01%), thus correlating these with aHUS. For C3G, an association was only found for RVs in C3 and the N-terminal C3b-binding or C-terminal nonsurface-associated regions of CFH In conclusion, the RV analyses showed nonrandom distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes.
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Síndrome Hemolítico Urémico Atípico/genética , Complemento C3/genética , Factor H de Complemento/genética , Vía Alternativa del Complemento/genética , Glomerulonefritis Membranoproliferativa/genética , Síndrome Hemolítico Urémico Atípico/patología , Complemento C3/metabolismo , Vía Alternativa del Complemento/fisiología , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Glomerulonefritis Membranoproliferativa/patología , Humanos , Masculino , Mutación Missense/genéticaRESUMEN
BACKGROUND: Genetic variation in complement genes is a predisposing factor for atypical hemolytic uremic syndrome (aHUS), a life-threatening thrombotic microangiopathy, however interpreting the effects of genetic variants is challenging and often ambiguous. METHODS: We analyzed 93 complement and coagulation genes in 400 patients with aHUS, using as controls 600 healthy individuals from Iowa and 63,345 non-Finnish European individuals from the Genome Aggregation Database. After adjusting for population stratification, we then applied the Fisher exact, modified Poisson exact, and optimal unified sequence kernel association tests to assess gene-based variant burden. We also applied a sliding-window analysis to define the frequency range over which variant burden was significant. RESULTS: We found that patients with aHUS are enriched for ultrarare coding variants in the CFH, C3, CD46, CFI, DGKE, and VTN genes. The majority of the significance is contributed by variants with a minor allele frequency of <0.1%. Disease-related variants tend to occur in specific complement protein domains of FH, CD46, and C3. We observed no enrichment for multiple rare coding variants in gene-gene combinations. CONCLUSIONS: In known aHUS-associated genes, variants with a minor allele frequency >0.1% should not be considered pathogenic unless valid enrichment and/or functional evidence are available. VTN, which encodes vitronectin, an inhibitor of the terminal complement pathway, is implicated as a novel aHUS-associated gene. Patients with aHUS are not enriched for multiple rare variants in complement genes. In aggregate, these data may help in directing clinical management of aHUS.
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Síndrome Hemolítico Urémico Atípico/genética , Adolescente , Adulto , Anciano , Síndrome Hemolítico Urémico Atípico/sangre , Factores de Coagulación Sanguínea/genética , Niño , Preescolar , Proteínas del Sistema Complemento/genética , Bases de Datos Genéticas , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Variación Genética , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mutación , Vitronectina/genética , Adulto JovenRESUMEN
Hereditary hearing loss is a clinically and genetically heterogeneous disorder. More than 80 genes have been implicated to date, and with the advent of targeted genomic enrichment and massively parallel sequencing (TGE+MPS) the rate of novel deafness-gene identification has accelerated. Here we report a family segregating post-lingual progressive autosomal dominant non-syndromic hearing loss (ADNSHL). After first excluding plausible variants in known deafness-causing genes using TGE+MPS, we completed whole exome sequencing in three hearing-impaired family members. Only a single variant, p.Arg185Pro in HOMER2, segregated with the hearing-loss phenotype in the extended family. This amino acid change alters a highly conserved residue in the coiled-coil domain of HOMER2 that is essential for protein multimerization and the HOMER2-CDC42 interaction. As a scaffolding protein, HOMER2 is involved in intracellular calcium homeostasis and cytoskeletal organization. Consistent with this function, we found robust expression in stereocilia of hair cells in the murine inner ear and observed that over-expression of mutant p.Pro185 HOMER2 mRNA causes anatomical changes of the inner ear and neuromasts in zebrafish embryos. Furthermore, mouse mutants homozygous for the targeted deletion of Homer2 present with early-onset rapidly progressive hearing loss. These data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action.
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Proteínas Portadoras/genética , Oído Interno/metabolismo , Exoma/genética , Pérdida Auditiva Sensorineural/genética , Animales , Proteínas Portadoras/biosíntesis , Cóclea/metabolismo , Cóclea/patología , Oído Interno/patología , Regulación de la Expresión Génica , Pérdida Auditiva Sensorineural/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas de Andamiaje Homer , Humanos , Ratones , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Estereocilios/genética , Estereocilios/patología , Pez Cebra , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/metabolismoRESUMEN
The thrombotic microangiopathies (TMAs) and C3 glomerulopathies (C3Gs) include a spectrum of rare diseases such as atypical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, C3GN, and dense deposit disease, which share phenotypic similarities and underlying genetic commonalities. Variants in several genes contribute to the pathogenesis of these diseases, and identification of these variants may inform the diagnosis and treatment of affected patients. We have developed and validated a comprehensive genetic panel that screens all exons of all genes implicated in TMA and C3G. The closely integrated pipeline implemented includes targeted genomic enrichment, massively parallel sequencing, bioinformatic analysis, and a multidisciplinary conference to analyze identified variants in the context of each patient's specific phenotype. Herein, we present our 1-year experience with this panel, during which time we studied 193 patients. We identified 17 novel and 74 rare variants, which we classified as pathogenic (11), likely pathogenic (12), and of uncertain significance (68). Compared with controls, patients with C3G had a higher frequency of rare and novel variants in C3 convertase (C3 and CFB) and complement regulator (CFH, CFI, CFHR5, and CD46) genes (P<0.05). In contrast, patients with TMA had an increase in rare and novel variants only in complement regulator genes (P<0.01), a distinction consistent with differing sites of complement dysregulation in these two diseases. In summary, we were able to provide a positive genetic diagnosis in 43% and 41% of patients carrying the clinical diagnosis of C3G and TMA, respectively.
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Enfermedades Renales/diagnóstico , Enfermedades Renales/genética , Glomérulos Renales , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/genética , Adolescente , Niño , Preescolar , Complemento C3 , Femenino , Pruebas Genéticas/métodos , Humanos , Enfermedades Renales/inmunología , MasculinoRESUMEN
Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy caused by uncontrolled activation of the alternative pathway of complement at the cell surface level that leads to microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. In approximately one half of affected patients, pathogenic loss-of-function variants in regulators of complement or gain-of-function variants in effectors of complement are identified, clearly implicating complement in aHUS. However, there are strong lines of evidence supporting the presence of additional genetic contributions to this disease. To identify novel aHUS-associated genes, we completed a comprehensive screen of the complement and coagulation pathways in 36 patients with sporadic aHUS using targeted genomic enrichment and massively parallel sequencing. After variant calling, quality control, and hard filtering, we identified 84 reported or novel nonsynonymous variants, 22 of which have been previously associated with disease. Using computational prediction methods, 20 of the remaining 62 variants were predicted to be deleterious. Consistent with published data, nearly one half of these 42 variants (19; 45%) were found in genes implicated in the pathogenesis of aHUS. Several genes in the coagulation pathway were also identified as important in the pathogenesis of aHUS. PLG, in particular, carried more pathogenic variants than any other coagulation gene, including three known plasminogen deficiency mutations and a predicted pathogenic variant. These data suggest that mutation screening in patients with aHUS should be broadened to include genes in the coagulation pathway.
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Coagulación Sanguínea/genética , Proteínas del Sistema Complemento/genética , Síndrome Hemolítico-Urémico/sangre , Síndrome Hemolítico-Urémico/genética , Mutación , Plasminógeno/deficiencia , Plasminógeno/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Síndrome Hemolítico Urémico Atípico , Niño , Preescolar , Vía Alternativa del Complemento/genética , Secuencia Conservada , Variaciones en el Número de Copia de ADN , Femenino , Pruebas Genéticas , Variación Genética , Síndrome Hemolítico-Urémico/etiología , Humanos , Masculino , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Microangiopatías Trombóticas/sangre , Microangiopatías Trombóticas/genética , Microangiopatías Trombóticas/inmunología , Adulto JovenRESUMEN
Hereditary hearing loss is extremely heterogeneous. Over 70 genes have been identified to date, and with the advent of massively parallel sequencing, the pace of novel gene discovery has accelerated. In a family segregating progressive autosomal-dominant nonsyndromic hearing loss (NSHL), we used OtoSCOPE® to exclude mutations in known deafness genes and then performed segregation mapping and whole-exome sequencing to identify a unique variant, p.Ser178Leu, in TBC1D24 that segregates with the hearing loss phenotype. TBC1D24 encodes a GTPase-activating protein expressed in the cochlea. Ser178 is highly conserved across vertebrates and its change is predicted to be damaging. Other variants in TBC1D24 have been associated with a panoply of clinical symptoms including autosomal recessive NSHL, syndromic hearing impairment associated with onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS syndrome), and a wide range of epileptic disorders.
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Proteínas Portadoras/genética , Genes Dominantes , Mutación , Secuencia de Aminoácidos , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Análisis Mutacional de ADN , Sordera/genética , Exoma , Femenino , Proteínas Activadoras de GTPasa , Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Proteínas de la Membrana , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso , Linaje , Alineación de SecuenciaRESUMEN
The application of whole genome sequencing is expanding in clinical diagnostics across various genetic disorders, and the significance of non-coding variants in penetrant diseases is increasingly being demonstrated. Therefore, it is urgent to improve the diagnostic yield by exploring the pathogenic mechanisms of variants in non-coding regions. However, the interpretation of non-coding variants remains a significant challenge, due to the complex functional regulatory mechanisms of non-coding regions and the current limitations of available databases and tools. Hence, we develop the non-coding variant annotation database (NCAD, http://www.ncawdb.net/), encompassing comprehensive insights into 665,679,194 variants, regulatory elements, and element interaction details. Integrating data from 96 sources, spanning both GRCh37 and GRCh38 versions, NCAD v1.0 provides vital information to support the genetic diagnosis of non-coding variants, including allele frequencies of 12 diverse populations, with a particular focus on the population frequency information for 230,235,698 variants in 20,964 Chinese individuals. Moreover, it offers prediction scores for variant functionality, five categories of regulatory elements, and four types of non-coding RNAs. With its rich data and comprehensive coverage, NCAD serves as a valuable platform, empowering researchers and clinicians with profound insights into non-coding regulatory mechanisms while facilitating the interpretation of non-coding variants.
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Bases de Datos Genéticas , Secuencias Reguladoras de Ácidos Nucleicos , Humanos , Anotación de Secuencia Molecular , Frecuencia de los Genes , Secuencias Reguladoras de Ácidos Nucleicos/genética , Variación Genética/genéticaRESUMEN
BACKGROUND: A comprehensive understanding of the genetic basis of rare diseases and their regulatory mechanisms is essential for human molecular genetics. However, the genetic mutant spectrum of pathogenic genes within the Chinese population remains underrepresented. Here, we reported previously unreported functional ABHD12 variants in two Chinese families and explored the correlation between genetic polymorphisms and phenotypes linked to PHARC syndrome. METHODS: Participants with biallelic pathogenic ABHD12 variants were recruited from the Chinese Deafness Genetics Cohort. These participants underwent whole-genome sequencing. Subsequently, a comprehensive literature review was conducted. RESULTS: Two Han Chinese families were identified, one with a compound heterozygous variant and the other with a novel homozygous variant in ABHD12. Among 65 PHARC patients, including 62 from the literature and 3 from this study, approximately 90% (57 out of 63) exhibited hearing loss, 82% (50 out of 61) had cataracts, 82% (46 out of 56) presented with retinitis pigmentosa, 79% (42 out of 53) experienced polyneuropathy, and 63% (36 out of 57) displayed ataxia. Seventeen different patterns were observed in the five main phenotypes of PHARC syndrome. A total of 33 pathogenic variants were identified in the ABHD12. Compared with other genotypes, individuals with biallelic truncating variants showed a higher incidence of polyneuropathy (p = 0.006), but no statistically significant differences were observed in the incidence of hearing loss, ataxia, retinitis pigmentosa and cataracts. CONCLUSIONS: The diagnosis of PHARC syndrome is challenging because of its genetic heterogeneity. Therefore, exploring novel variants and establishing genotype-phenotype correlations can significantly enhance gene diagnosis and genetic counseling for this complex disease.
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Ataxia , Catarata , Estudios de Asociación Genética , Monoacilglicerol Lipasas , Linaje , Fenotipo , Polineuropatías , Retinitis Pigmentosa , Humanos , Masculino , Femenino , Ataxia/genética , Catarata/genética , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/patología , Polineuropatías/genética , Monoacilglicerol Lipasas/genética , Mutación , Adulto , Niño , Adolescente , GenotipoRESUMEN
Previous studies on genetic diseases predominantly focused on protein-coding variations, overlooking the vast noncoding regions in the human genome. The development of high-throughput sequencing technologies and functional genomics tools has enabled the systematic identification of functional noncoding variants. These variants can impact gene expression, regulation, and chromatin conformation, thereby contributing to disease pathogenesis. Understanding the mechanisms that underlie the impact of noncoding variants on genetic diseases is indispensable for the development of precisely targeted therapies and the implementation of personalized medicine strategies. The intricacies of noncoding regions introduce a multitude of challenges and research opportunities. In this review, we introduce a spectrum of noncoding variants involved in genetic diseases, along with research strategies and advanced technologies for their precise identification and in-depth understanding of the complexity of the noncoding genome. We will delve into the research challenges and propose potential solutions for unraveling the genetic basis of rare and complex diseases.
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Variación Genética , Genómica , Humanos , Variación Genética/genética , Medicina de Precisión , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma CompletoRESUMEN
BACKGROUND: The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines recommend using variant enrichment among cases as "strong" evidence for pathogenicity per the PS4 criterion. However, quantitative support for PS4 thresholds from real-world Mendelian case-control cohorts is lacking. METHODS: To address this gap, we evaluated and established PS4 thresholds using data from the Chinese Deafness Genetics Consortium. A total of 9,050 variants from 13,845 patients with hearing loss (HL) and 6,570 ancestry-matched controls were analyzed. Positive likelihood ratio and local positive likelihood ratio values were calculated to determine the thresholds corresponding to each strength of evidence across three variant subsets. RESULTS: In subset 1, consisting of variants present in both cases and controls with an allele frequency (AF) in cases ≥ 0.0005, an odds ratio (OR) ≥ 6 achieved strong evidence, while OR ≥ 3 represented moderate evidence. For subset 2, which encompassed variants present in both cases and controls with a case AF < 0.0005, and subset 3, comprising variants found only in cases and absent from controls, we defined the PS4_Supporting threshold (OR > 2.27 or allele count ≥ 3) and the PS4_Moderate threshold (allele count ≥ 6), respectively. Reanalysis applying the adjusted PS4 criteria changed the classification of 15 variants and enabled diagnosis of an additional four patients. CONCLUSIONS: Our study quantified evidence strength thresholds for variant enrichment in genetic HL cases, highlighting the importance of defining disease/gene-specific thresholds to improve the precision and accuracy of clinical genetic testing.
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Variación Genética , Pérdida Auditiva , Humanos , Virulencia , Genoma Humano , Pruebas Genéticas , Pérdida Auditiva/genéticaRESUMEN
Atypical hemolytic uremic syndrome (aHUS) is a rare renal disease (two per one million in the USA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Both sporadic (80% of cases) and familial (20% of cases) forms are recognized. The study of familial aHUS has implicated genetic variation in multiple genes in the complement system in disease pathogenesis, helping to define the mechanism whereby complement dysregulation at the cell surface level leads to both sporadic and familial disease. This understanding has culminated in the use of Eculizumab as first-line therapy in disease treatment, significantly changing the care and prognosis of affected patients. However, even with this bright outlook, major challenges remain to understand the complexity of aHUS at the genetic level. It is possible that a more detailed picture of aHUS can be translated to an improved understanding of disease penetrance, which is highly variable, and response to therapy, both in the short and long terms.
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Síndrome Hemolítico-Urémico/genética , Síndrome Hemolítico-Urémico/inmunología , Síndrome Hemolítico Urémico Atípico , Proteínas del Sistema Complemento/genética , Proteínas del Sistema Complemento/inmunología , Variación Genética , HumanosRESUMEN
In clinical genetic testing, checking the concordance between self-reported gender and genotype-inferred gender from genomic data is a significant quality control measure because mismatched gender due to sex chromosomal abnormalities or misregistration of clinical information can significantly affect molecular diagnosis and treatment decisions. Targeted gene sequencing (TGS) is widely recommended as a first-tier diagnostic step in clinical genetic testing. However, the existing gender-inference tools are optimized for whole genome and whole exome data and are not adequate and accurate for analyzing TGS data. In this study, we validated a new gender-inference tool, seGMM, which uses unsupervised clustering (Gaussian mixture model) to determine the gender of a sample. The seGMM tool can also identify sex chromosomal abnormalities in samples by aligning the sequencing reads from the genotype data. The seGMM tool consistently demonstrated >99% gender-inference accuracy in a publicly available 1,000-gene panel dataset from the 1,000 Genomes project, an in-house 785 hearing loss gene panel dataset of 16,387 samples, and a 187 autism risk gene panel dataset from the Autism Clinical and Genetic Resources in China (ACGC) database. The performance and accuracy of seGMM was significantly higher for the targeted gene sequencing (TGS), whole exome sequencing (WES), and whole genome sequencing (WGS) datasets compared to the other existing gender-inference tools such as PLINK, seXY, and XYalign. The results of seGMM were confirmed by the short tandem repeat analysis of the sex chromosome marker gene, amelogenin. Furthermore, our data showed that seGMM accurately identified sex chromosomal abnormalities in the samples. In conclusion, the seGMM tool shows great potential in clinical genetics by determining the sex chromosomal karyotypes of samples from massively parallel sequencing data with high accuracy.
RESUMEN
Vitamin D deficiency is a common public health problem in the US. It is related to the high risk of rickets, osteoporosis and other diseases. Currently, serum 25-hydroxy vitamin D [25(OH)D] concentration is the best indicator of vitamin D status, and determination of its deficiency or sufficiency. This level has high heritability (28-80%). However, genes contributing to the wide variation in serum 25(OH)D are generally unknown. In this study, we screened nine important genes in vitamin D metabolic pathways using 49 single nucleotide polymorphism (SNP) markers in a group of 156 unrelated healthy Caucasian subjects. Significant confounding factors that may affect serum 25(OH)D variations were used as covariates for the association analyses. An association test for quantitative trait was performed to evaluate the association between candidate genes and serum 25(OH)D levels. Permutation was conducted for correcting multiple testing problems. Evidence of association was observed at SNPs in the CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1) and the GC (vitamin D binding protein) gene. Next, we performed a replication study for six promising SNPs in the gene CYP2R1 and GC, using another group of 340 unrelated healthy Caucasian subjects. Association analyses were conducted in the replication cohort (n = 340) and the pooled cohort (n = 496). The CYP2R1 gene and the GC gene remain significant in the pooled cohort. The results suggest that the CYP2R1 and GC genes may contribute to the variation of serum 25(OH)D levels in healthy populations.
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Colestanotriol 26-Monooxigenasa/genética , Polimorfismo de Nucleótido Simple , Proteína de Unión a Vitamina D/genética , Vitamina D/análogos & derivados , Población Blanca/genética , Análisis de Varianza , Factores de Confusión Epidemiológicos , Estudios Transversales , Familia 2 del Citocromo P450 , Estudio de Asociación del Genoma Completo , Humanos , Valores de Referencia , Vitamina D/sangreAsunto(s)
Síndrome Hemolítico Urémico Atípico/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Adolescente , Biomarcadores/metabolismo , Estudios de Casos y Controles , Estudios de Cohortes , Activación de Complemento , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Valor Predictivo de las Pruebas , Trombocitopenia/metabolismo , Adulto JovenRESUMEN
Previously, we mapped the DFNA52 (OMIM: 607683) locus to an 8.8 cM interval between STR D5S2056 and D5S638 on human chromosome 5q31.1-q32 in a large consanguineous Chinese family with congenital sensorineural hearing loss. Positional candidate cloning approach was applied to analyze the candidate genes in this region. We analyzed 20 genes according to cochlear expression pattern, which were also located in the DFNA52 interval as candidate genes. Sequencing of the coding and splice site regions of these genes did not reveal any potentially pathogenic mutations segregating with the disease, implying that none of these genes are likely virulence gene for DFNA52.
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Mapeo Cromosómico/métodos , Cromosomas Humanos Par 5/genética , Proteínas de Unión al ADN/genética , Mutación/genética , Secuencia de Bases , Femenino , Predisposición Genética a la Enfermedad/genética , Pérdida Auditiva/genética , Humanos , Masculino , Linaje , Reacción en Cadena de la PolimerasaRESUMEN
To localize the pathogenic genes of autosomal dominant ichthyosis vulgaris, we ascertained two ichthyosis vulgaris families from Hunan Province. Venous blood samples were collected from affected and unaffected family members and genomic DNA was extracted. We then performed genome scan and linkage analysis using microsatellite markers around known ichthyosis vulgaris loci in chromosomes 1 and 10. In family 1, the locus linked to ichthyosis vulgaris was located near D1S498 (1q21), which overlapped with known ichthyosis vulgaris loci. In family 2, however, all known loci for ichthyosis vulgaris were excluded and the new locus remains to be identified.
Asunto(s)
Mapeo Cromosómico/métodos , Ictiosis Vulgar/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 10/genética , Femenino , Ligamiento Genético/genética , Humanos , Masculino , Repeticiones de Microsatélite/genética , LinajeRESUMEN
SUMMARY: Three genes, including EGFR (epidermal growth factor receptor), CALM3 (calmodulin 3, calcium-modulated protein 3) and SMARCD1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily d member 1), play different roles in bone and/or fat metabolism in Caucasian women. In this population-based investigation of 870 unrelated postmenopausal Caucasian women, CALM3 polymorphisms were significantly associated with femoral neck bone mineral density (FNK BMD), hip BMD and spine BMD. Age and tobacco status also affected BMD levels and were therefore corrected for in our statistical analysis. INTRODUCTION: EGFR, CALM3 and SMARCD1 play roles in bone and/or fat metabolism. However, the correlations between the polymorphisms of these three genes and body composition levels, including BMD, remain to be determined. MATERIALS AND METHODS: A population-based investigation of 870 white women was conducted. Forty-four SNPs (single nucleotide polymorphisms) in EGFR, CALM3 and SMARCD1 were chosen by the software, including those of potential functional importance. The candidate SNPs were genotyped by the KASPar assay for an association analysis with body composition levels. The correlation analysis was assessed by the Pearson's product-moment correlation coefficient and Spearman rank-order correlation tests, and the family-wise error was corrected using the Wald test implemented in PLINK. RESULTS: The SNP rs12461917 in the 3'-flanking region of the CALM3 gene was significantly associated with FNK BMD (Pâ=â0.001), hip BMD (P<0.001) and spine BMD (Pâ=â0.001); rs11083838 in the 5'-flanking region of CALM3 gene was associated with spine BMD (Pâ=â0.009). After adjusting for multiple comparisons, rs12461917 remained significant (P-adjustedâ=â0.033 for FNK BMD, P-adjustedâ=â0.006 for hip BMD and P-adjustedâ=â0.018 for spine BMD). CONCLUSIONS: Our data show that polymorphisms of the CALM3 gene in Caucasian women may contribute to variations in the BMD of the hip, spine and femoral neck.