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1.
J Med Genet ; 56(8): 526-535, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30923172

RESUMO

BACKGROUND: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies. METHODS: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA. RESULTS: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation. CONCLUSION: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.

3.
Genet Med ; 20(7): 745-753, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29261186

RESUMO

PURPOSE: Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies. METHODS: We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia. RESULTS: A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB-related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort. CONCLUSION: Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power-but also the challenges-of WES in prenatal diagnosis.

4.
Acta Neuropathol ; 134(6): 889-904, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28685322

RESUMO

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.


Assuntos
Heterozigoto , Mutação , Miopatias Congênitas Estruturais/diagnóstico , Proteínas Tirosina Fosfatases não Receptoras/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Miopatias Congênitas Estruturais/fisiopatologia , Fenótipo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Índice de Gravidade de Doença
6.
Hematol Rep ; 7(2): 5729, 2015 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-26330998

RESUMO

Multiple myeloma (MM) is a neoplasm of plasma cells within the bone marrow. A major impact on improving survival in MM has been the use of the boronic acid-derived proteasome inhibitor bortezomib, a first-in-class selective inhibitor of the 26S proteasome. Ocular side effects of bortezomib are rare. In this report, we present 2 patients with active MM in whom persistent chalazia became a therapy-interfering complication of treatment with bortezomib. Both patients had relapsed ISS III B kappa light chain myeloma, and they were responding to treatment with bortezomib until chalazia - which caused intolerable discomfort - started. In both patients discontinuation of bortezomib was necessary for chalazia to heal, and restarting of bortezomib was associated with relapse of chalazia.

7.
Eur J Med Genet ; 55(4): 269-73, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22425634

RESUMO

We report the prenatal diagnosis of a 12q22q23.2 de novo interstitial deletion performed by array based comparative genomic hybridization (array CGH) in a fetus with cystic hygroma colli, intrauterine growth retardation, microcephaly and micrognathism. Haploinsufficiency for insuline-like growth factor 1 gene (IGF1), which is mapped in the deleted region, is suggested because of its implication in prenatal and postnatal growth and in neuronal maturation. This case demonstrates the contribution of array CGH in prenatal diagnosis for detecting small unbalanced chromosomal abnormalities in malformed fetuses and, subsequently, for genetic counselling.


Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 12/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Adulto , Sequência de Bases , Hibridização Genômica Comparativa , Feminino , Feto , Aconselhamento Genético , Haploinsuficiência , Humanos , Hibridização in Situ Fluorescente , Fator de Crescimento Insulin-Like I/deficiência , Fator de Crescimento Insulin-Like I/genética , Cariotipagem , Dados de Sequência Molecular , Gravidez , Diagnóstico Pré-Natal , Ultrassonografia Pré-Natal
8.
Urology ; 79(5): e75-6, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22088572

RESUMO

A 71-year-old man with a history of castration-refractory prostate cancer was initially treated with hormonal therapy. He responded with a decreasing prostate-specific antigen level and improved symptoms. Chemotherapy was initiated later, after an increasing prostate-specific antigen level and findings of distant metastases. Nine months after his initial diagnosis, he presented with a large multinodular perianal mass that was suspicious for primary anal cancer. Biopsy revealed poorly differentiated metastatic prostate carcinoma. The patient died 2 months after the initial presentation with perianal skin metastasis.


Assuntos
Neoplasias do Ânus/patologia , Neoplasias do Ânus/secundário , Carcinoma/patologia , Carcinoma/secundário , Neoplasias da Próstata/patologia , Idoso , Diagnóstico Diferencial , Humanos , Masculino
9.
Urology ; 74(4): 787-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19628273

RESUMO

A 65-year-old man with a history of Castleman's disease presented with abdominal and right flank pain. He denied any recent trauma. On admission, his hemoglobin was 7.0 g/dL, and the blood urea nitrogen and serum creatinine concentration was 30 and 1.62 mg/dL, respectively. Computed tomography of the patient's abdomen revealed a large right perinephric hematoma. The patient underwent emergency nephrectomy. Microscopic examination of the specimen revealed an incidental renal cell carcinoma.


Assuntos
Carcinoma de Células Renais/complicações , Hiperplasia do Linfonodo Gigante/complicações , Nefropatias/etiologia , Neoplasias Renais/complicações , Idoso , Humanos , Masculino , Ruptura Espontânea
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