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1.
Genet Med ; 23(8): 1492-1497, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33911214

RESUMO

PURPOSE: Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. METHODS: We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). RESULTS: We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. CONCLUSION: Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.


Assuntos
Epilepsia , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Adulto , Idoso , Epilepsia/diagnóstico , Epilepsia/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Cariotipagem , Sequenciamento do Exoma
2.
Biol Blood Marrow Transplant ; 23(9): 1582-1587, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28549770

RESUMO

Allogeneic hematopoietic cell transplantation (HCT) is an important treatment for many severe hematologic disorders; however, HCT can be associated with significant complications, including organ toxicity, graft-versus-host disease, and relapse. Another serious, but rare, complication is the transmission of hematologic and nonhematologic diseases from the donor to the recipient. With older donors, the risk of an abnormality may be increased. Here we describe the transmission of an inversion 3 constitutional cytogenetic abnormality from an unrelated donor to a recipient, and review the clinical implications of the discovery of donor-derived constitutional cytogenetic abnormalities.


Assuntos
Inversão Cromossômica , Cromossomos Humanos Par 3 , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Policitemia Vera/terapia , Doadores não Relacionados , Progressão da Doença , Humanos , Cariótipo , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Policitemia Vera/complicações , Policitemia Vera/genética , Policitemia Vera/patologia , Transplantados , Transplante Homólogo
3.
Ann Neurol ; 80(4)2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27543892

RESUMO

The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K(+) -channel, KV 1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow-up analysis of > 2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two-electrode voltage-clamp recordings of Xenopus laevis oocytes expressing mutant KV 1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism. Ann Neurol 2016.


Assuntos
Ataxia/genética , Deficiência Intelectual/genética , Canal de Potássio Kv1.2/genética , Paraplegia Espástica Hereditária/genética , Adulto , Animais , Ataxia/fisiopatologia , Criança , Exoma , Feminino , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Oócitos/metabolismo , Linhagem , Paraplegia Espástica Hereditária/fisiopatologia , Xenopus laevis , Adulto Jovem
4.
J Med Genet ; 52(4): 240-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25604083

RESUMO

BACKGROUND: SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia in combination with XY sex reversal. Studies in mice indicate that SOX9 acts as a testis-inducing transcription factor downstream of SRY, triggering Sertoli cell and testis differentiation. An SRY-dependent testis-specific enhancer for Sox9 has been identified only in mice. A previous study has implicated copy number variations (CNVs) of a 78 kb region 517-595 kb upstream of SOX9 in the aetiology of both 46,XY and 46,XX disorders of sex development (DSD). We wanted to better define this region for both disorders. RESULTS: By CNV analysis, we identified SOX9 upstream duplications in three cases of SRY-negative 46,XX DSD, which together with previously reported duplications define a 68 kb region, 516-584 kb upstream of SOX9, designated XXSR (XX sex reversal region). More importantly, we identified heterozygous deletions in four families with SRY-positive 46,XY DSD without skeletal phenotype, which define a 32.5 kb interval 607.1-639.6 kb upstream of SOX9, designated XY sex reversal region (XYSR). To localise the suspected testis-specific enhancer, XYSR subfragments were tested in cell transfection and transgenic experiments. While transgenic experiments remained inconclusive, a 1.9 kb SRY-responsive subfragment drove expression specifically in Sertoli-like cells. CONCLUSIONS: Our results indicate that isolated 46,XY and 46,XX DSD can be assigned to two separate regulatory regions, XYSR and XXSR, far upstream of SOX9. The 1.9 kb SRY-responsive subfragment from the XYSR might constitute the core of the Sertoli-cell enhancer of human SOX9, representing the so far missing link in the genetic cascade of male sex determination.


Assuntos
Variações do Número de Cópias de DNA , Transtornos do Desenvolvimento Sexual/genética , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição SOX9/genética , Animais , Linhagem Celular , Estudos de Coortes , Feminino , Humanos , Masculino , Camundongos , Linhagem
5.
Sci Rep ; 12(1): 13507, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931711

RESUMO

The 15q13.3 microdeletion has pleiotropic effects ranging from apparently healthy to severely affected individuals. The underlying basis of the variable phenotype remains elusive. We analyzed gene expression using blood from three individuals with 15q13.3 microdeletion and brain cortex tissue from ten mice Df[h15q13]/+. We assessed differentially expressed genes (DEGs), protein-protein interaction (PPI) functional modules, and gene expression in brain developmental stages. The deleted genes' haploinsufficiency was not transcriptionally compensated, suggesting a dosage effect may contribute to the pathomechanism. DEGs shared between tested individuals and a corresponding mouse model show a significant overlap including genes involved in monogenic neurodevelopmental disorders. Yet, network-wide dysregulatory effects suggest the phenotype is not caused by a single critical gene. A significant proportion of blood DEGs, silenced in adult brain, have maximum expression during the prenatal brain development. Based on DEGs and their PPI partners we identified altered functional modules related to developmental processes, including nervous system development. We show that the 15q13.3 microdeletion has a ubiquitous impact on the transcriptome pattern, especially dysregulation of genes involved in brain development. The high phenotypic variability seen in 15q13.3 microdeletion could stem from an increased vulnerability during brain development, instead of a specific pathomechanism.


Assuntos
Transtornos Cromossômicos , Transcriptoma , Animais , Encéfalo/metabolismo , Deleção Cromossômica , Transtornos Cromossômicos/metabolismo , Cromossomos Humanos Par 15/genética , Humanos , Deficiência Intelectual , Camundongos , Convulsões
6.
Int J Oncol ; 36(4): 929-40, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20198338

RESUMO

Since the first description of human fragile sites (FS) more than 40 years ago, a variety of substances were reported to induce chromosomal breaks at non-random, breakage-prone regions. According to information available from human genome browsers aphidicolin, an inhibitor of DNA replication induces 77 of 88 known common FS. However, in the literature additional FS are reported, which are also, at least in part, inducible by aphidicolin. To the best of our knowledge, here we present the first and largest ever done systematic, whole genome-directed and comprehensive screening for aphidicolin-inducible breakage-prone regions. The study was performed on stimulated peripheral blood lymphocytes of 3 unrelated healthy individuals. Twenty-five thousand metaphase spreads were analyzed and overall 22,537 FS located in 230 different loci were recorded. Sixty-one of those FS were never observed before and 52 were already previously reported but not included in genome browsers and yet verified. Interestingly, aphidicolin was able to induce all types of rare and common FS, suggesting that these breakage-prone regions are less dependent on the inducing chemicals than originally supposed. Overall, we provide the first comprehensive genome wide map for FS and studied possible correlations of chromosome length and GTG-banding level with FS-frequency. To handle FS better in future, an extension of the already existing alphabetical nomenclature for FS on single chromosomes is suggested.


Assuntos
Afidicolina/farmacologia , Sítios Frágeis do Cromossomo , Fragilidade Cromossômica , Cromossomos Humanos/efeitos dos fármacos , Genômica , Linfócitos/efeitos dos fármacos , Terminologia como Assunto , Células Cultivadas , Análise Citogenética , Feminino , Genômica/métodos , Humanos , Linfócitos/patologia , Metáfase
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