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1.
Nephrol Dial Transplant ; 37(2): 349-357, 2022 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-33306124

RESUMEN

BACKGROUND: Often only chronic kidney disease (CKD) patients with high likelihood of genetic disease are offered genetic testing. Early genetic testing could obviate the need for kidney biopsies, allowing for adequate prognostication and treatment. To test the viability of a 'genetics-first' approach for CKD, we performed genetic testing in a group of kidney transplant recipients aged <50 years, irrespective of cause of transplant. METHODS: From a cohort of 273 transplant patients, we selected 110 that were in care in the University Medical Center Utrecht, had DNA available and were without clear-cut non-genetic disease. Forty patients had been diagnosed with a genetic disease prior to enrollment; in 70 patients, we performed a whole-exome sequencing-based 379 gene panel analysis. RESULTS: Genetic analysis yielded a diagnosis in 51%. Extrapolated to the 273 patient cohort, who did not all fit the inclusion criteria, the diagnostic yield was still 21%. Retrospectively, in 43% of biopsied patients, the kidney biopsy would not have had added diagnostic value if genetic testing had been performed as a first-tier diagnostic. CONCLUSIONS: The burden of monogenic disease in transplant patients with end-stage kidney disease (ESKD) of any cause prior to the age of 50 years is between 21% and 51%. Early genetic testing can provide a non-invasive diagnostic, impacting prognostication and treatment, and obviating the need for an invasive biopsy. We conclude that in patients who expect to develop ESKD prior to the age of 50 years, genetic testing should be considered as first mode of diagnostics.


Asunto(s)
Fallo Renal Crónico , Insuficiencia Renal Crónica , Estudios de Cohortes , Pruebas Genéticas , Humanos , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/genética , Persona de Mediana Edad , Insuficiencia Renal Crónica/complicaciones , Estudios Retrospectivos
2.
Genet Med ; 20(5): 480-485, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29121006

RESUMEN

PurposeNoninvasive prenatal screening (NIPS) using cell-free DNA in maternal blood is highly sensitive for detecting fetal trisomies 21, 18, and 13. Using a genome-wide approach, other chromosome anomalies can also be detected. We report on the origin, frequency, and clinical significance of these other chromosome aberrations found in pregnancies at risk for trisomy 21, 18, or 13.MethodsWhole-genome shallow massively parallel sequencing was used and all autosomes were analyzed.ResultsIn 78 of 2,527 cases (3.1%) NIPS was indicative of trisomy 21, 18, or 13, and in 41 (1.6%) of other chromosome aberrations. The latter were of fetal (n = 10), placental (n = 22), maternal (n = 1) or unknown (n = 7). One case lacked cytogenetic follow-up. Nine of the 10 fetal cases were associated with an abnormal phenotype. Thirteen of the 22 (59%) placental aberrations were associated with fetal congenital anomalies and/or poor fetal growth (

Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Pruebas Genéticas , Diagnóstico Prenatal , Trisomía , Variaciones en el Número de Copia de ADN , Femenino , Pruebas Genéticas/métodos , Genómica/métodos , Humanos , Placenta/metabolismo , Embarazo , Resultado del Embarazo , Diagnóstico Prenatal/métodos , Secuenciación Completa del Genoma
3.
J Allergy Clin Immunol ; 133(2): 529-34, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24139496

RESUMEN

BACKGROUND: Primary immunodeficiency (PID) disorders are a heterogeneous group of inherited disorders caused by a variety of monogenetic immune defects. Thus far, mutations in more than 170 different genes causing PIDs have been described. A clear genotype-phenotype correlation is often not available, which makes a genetic diagnosis in patients with PIDs complex and laborious. OBJECTIVE: We sought to develop a robust, time-effective, and cost-effective diagnostic method to facilitate a genetic diagnosis in any of 170 known PID-related genes by using next-generation sequencing (NGS). METHODS: We used both targeted array-based and in-solution enrichment combined with a SOLiD sequencing platform and a bioinformatic pipeline developed in house to analyze genetic changes in the DNA of 41 patients with PIDs with known mutations and 26 patients with undiagnosed PIDs. RESULTS: This novel NGS-based method accurately detected point mutations (sensitivity and specificity >99% in covered regions) and exonic deletions (100% sensitivity and specificity). For the 170 genes of interest, the DNA coverage was greater than 20× in 90% to 95%. Nine PID-related genes proved not eligible for evaluation by using this NGS-based method because of inadequate coverage. The NGS method allowed us to make a genetic diagnosis in 4 of 26 patients who lacked a genetic diagnosis despite routine functional and genetic testing. Three of these patients proved to have an atypical presentation of previously described PIDs. CONCLUSION: This novel NGS tool facilitates accurate simultaneous detection of mutations in 161 of 170 known PID-related genes. In addition, these analyses will generate more insight into genotype-phenotype correlations for the different PID disorders.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Síndromes de Inmunodeficiencia/genética , Análisis de Secuencia de ADN , Adolescente , Adulto , Niño , Predisposición Genética a la Enfermedad , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Masculino , Mutación
4.
Kidney Int Rep ; 9(9): 2695-2704, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39291214

RESUMEN

Introduction: Genetic testing can reveal monogenic causes of kidney diseases, offering diagnostic, therapeutic, and prognostic benefits. Although single nucleotide variants (SNVs) and copy number variants (CNVs) can result in kidney disease, CNV analysis is not always included in genetic testing. Methods: We investigated the diagnostic value of CNV analysis in 2432 patients with kidney disease genetically tested at the University Medical Centre Utrecht between 2014 and May 2022. We combined previous diagnostic testing results, encompassing SNVs and CNVs, with newly acquired results based on retrospective CNV analysis. The reported yield considers both the American College of Medical Genetics and Genomics (ACMG) classification and whether the genotype actually results in disease. Results: We report a diagnostic yield of at least 23% for our complete diagnostic cohort. The total diagnostic yield based solely on CNVs was 2.4%. The overall contribution of CNV analysis, defined as the proportion of positive genetic tests requiring CNV analysis, was 10.5% and varied among different disease subcategories, with the highest impact seen in congenital anomalies of the kidney and urinary tract (CAKUT) and chronic kidney disease at a young age. We highlight the efficiency of exome-based CNV calling, which reduces the need for additional diagnostic tests. Furthermore, a complex structural variant, likely a COL4A4 founder variant, was identified. Additional findings unrelated to kidney diseases were reported in a small percentage of cases. Conclusion: In summary, this study demonstrates the substantial diagnostic value of CNV analysis, providing insights into its contribution to the diagnostic yield and advocating for its routine inclusion in genetic testing of patients with kidney disease.

5.
BMC Genomics ; 13: 391, 2012 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-22891612

RESUMEN

BACKGROUND: The turkey (Meleagris gallopavo) is an important agricultural species and the second largest contributor to the world's poultry meat production. Genetic improvement is attributed largely to selective breeding programs that rely on highly heritable phenotypic traits, such as body size and breast muscle development. Commercial breeding with small effective population sizes and epistasis can result in loss of genetic diversity, which in turn can lead to reduced individual fitness and reduced response to selection. The presence of genomic diversity in domestic livestock species therefore, is of great importance and a prerequisite for rapid and accurate genetic improvement of selected breeds in various environments, as well as to facilitate rapid adaptation to potential changes in breeding goals. Genomic selection requires a large number of genetic markers such as e.g. single nucleotide polymorphisms (SNPs) the most abundant source of genetic variation within the genome. RESULTS: Alignment of next generation sequencing data of 32 individual turkeys from different populations was used for the discovery of 5.49 million SNPs, which subsequently were used for the analysis of genetic diversity among the different populations. All of the commercial lines branched from a single node relative to the heritage varieties and the South Mexican turkey population. Heterozygosity of all individuals from the different turkey populations ranged from 0.17-2.73 SNPs/Kb, while heterozygosity of populations ranged from 0.73-1.64 SNPs/Kb. The average frequency of heterozygous SNPs in individual turkeys was 1.07 SNPs/Kb. Five genomic regions with very low nucleotide variation were identified in domestic turkeys that showed state of fixation towards alleles different than wild alleles. CONCLUSION: The turkey genome is much less diverse with a relatively low frequency of heterozygous SNPs as compared to other livestock species like chicken and pig. The whole genome SNP discovery study in turkey resulted in the detection of 5.49 million putative SNPs compared to the reference genome. All commercial lines appear to share a common origin. Presence of different alleles/haplotypes in the SM population highlights that specific haplotypes have been selected in the modern domesticated turkey.


Asunto(s)
Variación Genética , Polimorfismo de Nucleótido Simple , Pavos/genética , Animales , Cruzamiento , Biblioteca de Genes , Masculino , México , Filogenia , Análisis de Secuencia de ADN
6.
J Clin Invest ; 132(11)2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35642635

RESUMEN

Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9-mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases.


Asunto(s)
Síndrome de Mobius , Enfermedades Musculares , Animales , Humanos , Proteínas de la Membrana/genética , Ratones , Proteínas Musculares/genética , Enfermedades Musculares/genética , Síndrome de Pierre Robin
8.
BMC Genet ; 11: 11, 2010 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-20141624

RESUMEN

BACKGROUND: Although several genetic linkage maps of the chicken genome have been published, the resolution of these maps is limited and does not allow the precise identification of recombination hotspots. The availability of more than 3.2 million SNPs in the chicken genome and the recent advances in high throughput genotyping techniques enabled us to increase marker density for the construction of a high-resolution linkage map of the chicken genome. This high-resolution linkage map allowed us to study recombination hotspots across the genome between two chicken populations: a purebred broiler line and a broiler x broiler cross. In total, 1,619 animals from the two different broiler populations were genotyped with 17,790 SNPs. RESULTS: The resulting linkage map comprises 13,340 SNPs. Although 360 polymorphic SNPs that had not been assigned to a known chromosome on chicken genome build WASHUC2 were included in this study, no new linkage groups were found. The resulting linkage map is composed of 31 linkage groups, with a total length of 3,054 cM for the sex-average map of the combined population. The sex-average linkage map of the purebred broiler line is 686 cM smaller than the linkage map of the broiler x broiler cross. CONCLUSIONS: In this study, we present a linkage map of the chicken genome at a substantially higher resolution than previously published linkage maps. Regional differences in recombination hotspots between the two mapping populations were observed in several chromosomes near the telomere of the p arm; the sex-specific analysis revealed that these regional differences were mainly caused by female-specific recombination hotspots in the broiler x broiler cross.


Asunto(s)
Pollos/genética , Mapeo Cromosómico/métodos , Ligamiento Genético , Genética de Población , Recombinación Genética , Animales , Cruzamientos Genéticos , Femenino , Genotipo , Masculino , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN
9.
BMC Genomics ; 9: 391, 2008 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-18713476

RESUMEN

BACKGROUND: One of the loci responsible for feather development in chickens is K. The K allele is partially dominant to the k+ allele and causes a retard in the emergence of flight feathers at hatch. The K locus is sex linked and located on the Z chromosome. Therefore, the locus can be utilized to produce phenotypes that identify the sexes of chicks at hatch. Previous studies on the organization of the K allele concluded the integration of endogenous retrovirus 21 (ev21) into one of two large homologous segments located on the Z chromosome of late feathering chickens. In this study, a detailed molecular analysis of the K locus and a DNA test to distinguish between homozygous and heterozygous late feathering males are presented. RESULTS: The K locus was investigated with quantitative PCR by examining copy number variations in a total of fourteen markers surrounding the ev21 integration site. The results showed a duplication at the K allele and sequence analysis of the breakpoint junction indicated a tandem duplication of 176,324 basepairs. The tandem duplication of this region results in the partial duplication of two genes; the prolactin receptor and the gene encoding sperm flagellar protein 2. Sequence analysis revealed that the duplication is similar in Broiler and White Leghorn. In addition, twelve late feathering animals, including Broiler, White Leghorn, and Brown Layer lines, contained a 78 bp breakpoint junction fragment, indicating that the duplication is similar in all breeds. The breakpoint junction was used to develop a TaqMan-based quantitative PCR test to allow distinction between homozygous and heterozygous late feathering males. In total, 85.3% of the animals tested were correctly assigned, 14.7% were unassigned and no animals were incorrectly assigned. CONCLUSION: The detailed molecular analysis presented in this study revealed the presence of a tandem duplication in the K allele. The duplication resulted in the partial duplication of two genes; the prolactin receptor and the gene encoding sperm flagellar protein 2. Furthermore, a DNA test was developed to distinguish between homozygous and heterozygous late feathering males.


Asunto(s)
Pollos/genética , Plumas/crecimiento & desarrollo , Duplicación de Gen , Receptores de Prolactina/genética , Alelos , Animales , Pollos/crecimiento & desarrollo , ADN/genética , Roturas del ADN , Femenino , Dosificación de Gen , Tamización de Portadores Genéticos , Marcadores Genéticos , Homocigoto , Masculino , Fenotipo , Reacción en Cadena de la Polimerasa , Sensibilidad y Especificidad , Lugares Marcados de Secuencia , Caracteres Sexuales , Cromosomas Sexuales/genética , Secuencias Repetidas en Tándem
10.
Clin Case Rep ; 6(5): 788-791, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29744057

RESUMEN

One of the confounders in noninvasive prenatal testing (NIPT) is the vanishing twin phenomenon. Prolonged contribution to the maternal Cell-free DNA (cfDNA) pool by cytotrophoblasts representing a demised, aneuploid cotwin may lead to a false-positive outcome for a normal, viable twin. We show that a vanishing trisomy-14 twin contributes to cfDNA for more than 2 weeks after demise.

11.
Clin Case Rep ; 3(6): 489-91, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26185654

RESUMEN

Noninvasive prenatal testing (NIPT) and direct karyotyping of cytotrophoblast were normal for a male fetus, but cultured chorionic villus mesenchymal cells and umbilical cord fibroblasts showed nonmosaic trisomy 18. This observation provides direct evidence for the cytotrophoblastic origin of cell-free fetal DNA and yields a biological explanation for falsely reassuring NIPT results.

12.
PLoS One ; 7(2): e32720, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22384281

RESUMEN

Identifying genomics regions that are affected by selection is important to understand the domestication and selection history of the domesticated chicken, as well as understanding molecular pathways underlying phenotypic traits and breeding goals. While whole-genome approaches, either high-density SNP chips or massively parallel sequencing, have been successfully applied to identify evidence for selective sweeps in chicken, it has been difficult to distinguish patterns of selection and stochastic and breed specific effects. Here we present a study to identify selective sweeps in a large number of chicken breeds (67 in total) using a high-density (58 K) SNP chip. We analyzed commercial chickens representing all major breeding goals. In addition, we analyzed non-commercial chicken diversity for almost all recognized traditional Dutch breeds and a selection of representative breeds from China. Based on their shared history or breeding goal we in silico grouped the breeds into 14 breed groups. We identified 396 chromosomal regions that show suggestive evidence of selection in at least one breed group with 26 of these regions showing strong evidence of selection. Of these 26 regions, 13 were previously described and 13 yield new candidate genes for performance traits in chicken. Our approach demonstrates the strength of including many different populations with similar, and breed groups with different selection histories to reduce stochastic effects based on single populations.


Asunto(s)
Genoma , Alelos , Animales , Cruzamiento , Pollos , China , ADN/metabolismo , Marcadores Genéticos/genética , Genotipo , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Modelos Genéticos , Modelos Estadísticos , Filogenia , Polimorfismo de Nucleótido Simple , Selección Genética , Programas Informáticos , Especificidad de la Especie
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