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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 724-726, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302921

RESUMO

OBJECTIVE: To explore the molecular mechanism of a girl with developmental delay and intellectual disability. METHODS: Chromosomal karotypes of the child and her parents were analyzed with routine G-banding method. Their genomic DNA was also analyzed with array comparative genomic hybridization (aCGH) for chromosomal duplications/deletions. RESULTS: No karyotypic abnormality was detected in the child and her parents, while aCGH has identified a de novo 3.37 Mb deletion at 17p11.2 in the child. CONCLUSION: The child was diagnosed with Smith-Magenis syndrome, for which RAI1 may be the causative gene.


Assuntos
Síndrome de Smith-Magenis/genética , Criança , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 17/genética , Hibridização Genômica Comparativa , Feminino , Humanos , Cariotipagem
2.
Genome Med ; 11(1): 12, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819258

RESUMO

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Mutação INDEL , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Síndrome de Smith-Magenis/patologia , Fatores de Transcrição/metabolismo , Adulto Jovem
3.
PLoS Genet ; 15(1): e1007879, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653500

RESUMO

Variably expressive copy-number variants (CNVs) are characterized by extensive phenotypic heterogeneity of neuropsychiatric phenotypes. Approaches to identify single causative genes for these phenotypes within each CNV have not been successful. Here, we posit using multiple lines of evidence, including pathogenicity metrics, functional assays of model organisms, and gene expression data, that multiple genes within each CNV region are likely responsible for the observed phenotypes. We propose that candidate genes within each region likely interact with each other through shared pathways to modulate the individual gene phenotypes, emphasizing the genetic complexity of CNV-associated neuropsychiatric features.


Assuntos
Variações do Número de Cópias de DNA/genética , Estudos de Associação Genética , Heterogeneidade Genética , Predisposição Genética para Doença , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Duplicação Cromossômica/genética , Regulação da Expressão Gênica , Humanos , Fenótipo , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/fisiopatologia , Síndrome de Sotos/genética , Síndrome de Sotos/fisiopatologia , Síndrome de Williams/genética , Síndrome de Williams/fisiopatologia
4.
Ann Hematol ; 97(12): 2269-2278, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30315344

RESUMO

Chronic lymphocytic leukemia (CLL), a disorder for which B cell heterogeneity and increased cellular proliferation play central pathogenic roles, displays several genetic abnormalities that are associated with poor prognosis and have therapeutic implications. In this review, we discuss the prognostic role and therapeutic implications of chromosome 17p deletions and TP53 mutations in CLL. Unlike other recurrent genetic abnormalities, the frequency of TP53 alterations is relatively low in newly diagnosed patients, but increases sharply with disease progression, which suggests that these alterations represent an evolutionary mechanism of resistance. In comparison with patients without such abnormalities, those with 17p deletions and TP53 mutations have lower response rates and more aggressive disease. One important consequence of the diverse molecular mechanisms that affect the TP53 pathway is the need to assess both the presence of 17p deletion and TP53 mutations before treatment initiation. Several authors have attempted to incorporate TP53 abnormalities in different prognostic models for CLL, and the recent International Prognostic Index for Chronic Lymphocytic Leukemia formally considers patients with TP53 abnormalities (deletion 17p or TP53 mutation or both) as high-risk. Several novel agents may improve results in patients with CLL, including in those with TP53 mutations. Ibrutinib, idelalisib, and venetoclax have been approved in various settings and countries for treatment of CLL. Further progress in targeted therapy and judicious use of chemotherapy, monoclonal antibodies, and reduced-intensity allogeneic transplantation will provide patients with CLL in general, and those with TP53 abnormalities in particular, with a better prognosis.


Assuntos
Antineoplásicos/uso terapêutico , Deleção Cromossômica , Leucemia Linfocítica Crônica de Células B , Síndrome de Smith-Magenis , Transplante de Células-Tronco , Proteína Supressora de Tumor p53/genética , Aloenxertos , Cromossomos Humanos Par 17/genética , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/terapia , Prognóstico , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/terapia
5.
Mol Med Rep ; 18(1): 981-986, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29845227

RESUMO

The genetic basis of congenital mental retardation includes chromosomal anomalies and single gene mutations. In addition to chromosome microarray analysis, next­generation sequencing (NGS) and Sanger sequencing have additionally been applied to identify single gene mutations. However, no methods exist to identify the cause of an anomaly in one step. The present study applied an improved targeted NGS method to diagnose an 8­year­old Chinese Han female with mental retardation in one step. The microdeletion 17p11.2 was successfully detected by the improved targeted NGS and no single gene mutations were identified. The same microdeletion was verified using low coverage whole­genome sequencing. Fertility guidance was also given to the patient's parents. In the present study, an improved targeted NGS method was applied to diagnose non­syndromic mental retardation of unknown cause in one step. This improved method has the potential to be developed into a screening panel for the effective diagnosis of genetic abnormalities in non­syndromic mental retardation and other congenital anomalies.


Assuntos
Deleção Cromossômica , Sequenciamento de Nucleotídeos em Larga Escala , Deficiência Intelectual , Síndrome de Smith-Magenis , Criança , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética
6.
Pediatr Ann ; 47(5): e198-e203, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29750287

RESUMO

This review summarizes common microdeletion and microduplication syndromes and highlights important updates in patient-care needs for people with these conditions (22q11.2, 7q11.23, 17p11.2, and 16p11.2). These conditions are in chromosomal "hotspots" and have an estimated prevalence of 1 in 1,000 to 1 in 25,000. Some conditions have possible increased or decreased genetic risk of schizophrenia (22q11.2 deletion and duplication), or risk of aortic dilation (7q11.23 duplication) versus aortic stenosis (7q11.23 deletion). Many of these conditions are associated with developmental delay, autism, and/or multiple congenital anomalies and would not be detected with a karyotype. Chromosomal microarray analysis will detect all these conditions with a single screening test, allowing for the appropriate diagnosis and management of these patients. [Pediatr Ann. 2018;47(5):e198-e203.].


Assuntos
Anormalidades Múltiplas , Transtorno Autístico , Deleção Cromossômica , Transtornos Cromossômicos , Duplicação Cromossômica , Síndrome de DiGeorge , Deficiência Intelectual , Síndrome de Smith-Magenis , Síndrome de Williams , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/terapia , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Transtorno Autístico/terapia , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/terapia , Duplicação Cromossômica/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 7 , Variações do Número de Cópias de DNA , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/terapia , Testes Genéticos , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/terapia , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/terapia , Síndrome de Williams/diagnóstico , Síndrome de Williams/genética , Síndrome de Williams/terapia
7.
J Hum Genet ; 63(7): 795-801, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29691480

RESUMO

Multiple genomic disorders result from recurrent deletions or duplications between low copy repeat (LCR) clusters, mediated by nonallelic homologous recombination. These copy number variants (CNVs) often exhibit variable expressivity and/or incomplete penetrance. However, the population prevalence of many genomic disorders has not been estimated accurately. A subset of genomic disorders similarly characterized by CNVs between LCRs have been studied epidemiologically, including Williams-Beuren syndrome (7q11.23), Smith-Magenis syndrome (17p11.2), velocardiofacial syndrome (22q11.21), Prader-Willi/Angelman syndromes (15q11.2q12), 17q12 deletion syndrome, and Charcot-Marie-Tooth neuropathy type 1/hereditary neuropathy with liability to pressure palsy (PMP22, 17q11.2). We have generated a method to estimate prevalence of highly penetrant genomic disorders by (1) leveraging epidemiological data for genomic disorders with previously reported prevalence estimates, (2) obtaining chromosomal microarray data on genomic disorders from a large medical genetics clinic; and (3) utilizing these in a linear regression model to determine the prevalence of this syndromic copy number change among the general population. Using our algorithm, the prevalence for five clinically relevant recurrent genomic disorders: 1q21.1 microdeletion (1/6882 live births) and microduplication syndromes (1/6309), 15q13.3 microdeletion syndrome (1/5525), and 16p11.2 microdeletion (1/3021) and microduplication syndromes (1/4216), were determined. These findings will inform epidemiological strategies for evaluating those conditions, and our method may be useful to evaluate the prevalence of other highly penetrant genomic disorders.


Assuntos
Doença de Charcot-Marie-Tooth/epidemiologia , Síndrome de DiGeorge/epidemiologia , Genoma Humano , Modelos Genéticos , Síndrome de Prader-Willi/epidemiologia , Síndrome de Smith-Magenis/epidemiologia , Síndrome de Williams/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Deleção Cromossômica , Duplicação Cromossômica , Mapeamento Cromossômico , Variações do Número de Cópias de DNA , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/patologia , Humanos , Análise em Microsséries , Epidemiologia Molecular , Penetrância , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/patologia , Prevalência , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/patologia , Síndrome de Williams/genética , Síndrome de Williams/patologia
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 34(5): 695-698, 2017 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-28981936

RESUMO

OBJECTIVE: To analyze a child with facial abnormalities with combined cytogenetic and molecular techniques and delineate its clinical phenotype. METHODS: Neuropsychological profile of the child was analyzed. Color Doppler, CT and MRI were used for detecting the nodules in the body. Conventional peripheral blood karyotypes of the child and his parents were analyzed with G-banding. Array-comparative genomic hybridization (aCGH) was performed to detect minor structural chromosomal abnormalities. RESULTS: The child had mental retardation, maxillofacial dysmorphism on the right side, and irregular solid nodules on the back. The karyotypes of the child and his parents were all normal, while aCGH has identified a de novo constitutive 1.2 Mb deletion at 17q11.2 in the child. The aCGH results of his parents were normal. CONCLUSION: The de novo 17q11.2 microdeletion probably underlies the facial abnormalities and neurofibromatosis in the patient.


Assuntos
Síndrome de Smith-Magenis/genética , Pré-Escolar , Bandeamento Cromossômico , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Hibridização Genômica Comparativa , Humanos , Deficiência Intelectual/genética , Cariotipagem , Masculino , Anormalidades Maxilofaciais/genética , Fenótipo
9.
Breast ; 34: 65-72, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28521178

RESUMO

PURPOSE: The new ASCO/CAP guidelines published in 2013 (AC2013) significantly modified the scoring criteria for HER2-FISH, introducing the most controversial change to the HER2-equivocal category. We retrospectively evaluated the impact of AC2013 in a cohort of consecutive invasive breast cancers (IBCs) analyzed with frontline dual-color FISH. METHODS: 2788 consecutive IBCs were reclassified based on the AC2013 guidelines. Clinico-pathological features of equivocal IBCs were compared with HER2-negative and HER2-positive IBCs. FISH HER2-equivocal cases underwent reflex tests: HER2-IHC, RARA-FISH, and SMS-FISH. Overall and disease-free survivals were evaluated in AC2007 HER2-positive patients treated with trastuzumab and in patients that became eligible for target-therapy according to AC2013. RESULTS: Two-hundred HER2-negative cases (7.2%) were classified differently, following AC2013: 0.3% (8/2788) became HER2-positive and 6.9% (192/2788) HER2-equivocal. AC2013, compared with AC2007, significantly increased initial HER2-equivocal cases (6.9%vs1.6%, p < 0.001). AC2013 equivocal-IBCs affected older patients and showed pathological features between HER2-negative and HER2-positive IBCs. After reflex tests, 102 of the 190 equivocal cases (53.7%) were reclassified as HER2-positive, 51 (26.8%) as negative and 37 (19.5%) as equivocal. IHC tested negative in 44.7% of cases, whereas SMS-FISH showed the highest percentage of positive results (45.8%). Clinical outcomes showed no statistically significant differences. CONCLUSION: Overall, 80.5% of FISH-equivocal cases were solved with at least one reflex test and 3.6% of patients became AC2013 HER2-positive, therefore eligible for target-therapy, but showed clinical outcomes similar to HER2-positive patients treated with trastuzumab. Our data belittle the clinical impact of AC2013 HER2-equivocal reclassification; further prospective randomized clinical studies are necessary to support these findings.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Receptor ErbB-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Aberrações Cromossômicas , Cromossomos Humanos Par 17 , Intervalo Livre de Doença , Feminino , Dosagem de Genes , Testes Genéticos/normas , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Receptor ErbB-2/metabolismo , Receptor alfa de Ácido Retinoico/genética , Estudos Retrospectivos , Síndrome de Smith-Magenis/genética , Taxa de Sobrevida , Trastuzumab/uso terapêutico , Adulto Jovem
10.
Pediatr Neurosurg ; 52(3): 195-204, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28380489

RESUMO

Occurrence of moyamoya syndrome in a patient with Smith-Magenis syndrome (SMS) has previously been reported once in a 10-year-old Asian female. We report a second case of moyamoya in a patient with SMS, in a now 25-year-old Asian female diagnosed with both conditions as a child. In addition to describing her medical and surgical history, we provide a detailed report of her omental transposition, in which the omental circulation was anastomosed to the superior thyroid artery and external jugular vein. To our knowledge, this is the first report of omental transposition for moyamoya in which omental vessels are anastomosed to vessels in the neck, as well as the second report of moyamoya in a patient with SMS.


Assuntos
Doença de Moyamoya/diagnóstico , Doença de Moyamoya/cirurgia , Procedimentos Neurocirúrgicos , Síndrome de Smith-Magenis/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Angiografia Cerebral , Revascularização Cerebral/métodos , Feminino , Artéria Gastroepiploica/cirurgia , Humanos , Deficiência Intelectual , Imagem por Ressonância Magnética , Doença de Moyamoya/diagnóstico por imagem
11.
J Speech Lang Hear Res ; 60(4): 1076-1087, 2017 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-28384694

RESUMO

Purpose: The purpose of this study was to describe the auditory phenotype of a large cohort with Smith-Magenis syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep disturbances, and a distinct behavioral phenotype. Method: Hearing-related data were collected for 133 individuals with SMS aged 1-49 years. Audiogram data (97 participants) were used for cross-sectional and longitudinal analyses. Caregivers completed a sound sensitivity survey for 98 individuals with SMS and a control group of 24 unaffected siblings. Results: Nearly 80% of participants with interpretable audiograms (n = 76) had hearing loss, which was typically slight to mild in degree. When hearing loss type could be determined (40 participants), sensorineural hearing loss (48.1%) occurred most often in participants aged 11-49 years. Conductive hearing loss (35.2%) was typically observed in children aged 1-10 years. A pattern of fluctuating and progressive hearing decline was documented. Hyperacusis was reported in 73.5% of participants with SMS compared with 12.5% of unaffected siblings. Conclusions: This study offers the most comprehensive characterization of the auditory phenotype of SMS to date. The auditory profile in SMS is multifaceted and can include a previously unreported manifestation of hyperacusis. Routine audiologic surveillance is recommended as part of standard clinical care.


Assuntos
Audição , Síndrome de Smith-Magenis/fisiopatologia , Adolescente , Adulto , Audiometria , Criança , Pré-Escolar , Estudos Transversais , Feminino , Perda Auditiva/classificação , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Humanos , Hiperacusia/genética , Hiperacusia/fisiopatologia , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Estudos Retrospectivos , Irmãos , Síndrome de Smith-Magenis/classificação , Síndrome de Smith-Magenis/genética , Inquéritos e Questionários , Adulto Jovem
12.
J Allergy Clin Immunol Pract ; 5(5): 1344-1350.e3, 2017 Sep - Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28286158

RESUMO

BACKGROUND: Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome 17p11.2 deletions that encompass not only the intellectual disability gene retinoic acid-induced 1 but also other genes associated with immunodeficiency, autoimmunity, and/or malignancy. OBJECTIVES: The goals of this study were to describe the immunological consequence of 17p11.2 deletions by determining the prevalence of immunological diseases in subjects with SMS and by assessing their immune systems via laboratory methods. METHODS: We assessed clinical histories of 76 subjects with SMS with heterozygous 17p11.2 deletions and performed in-depth immunological testing on 25 representative cohort members. Laboratory testing included determination of serum antibody concentrations, vaccine titers, and lymphocyte subset frequencies. Detailed reactivity profiles of SMS serum antibodies were performed using custom-made antigen microarrays. RESULTS: Of 76 subjects with SMS, 74 reported recurrent infections including otitis (88%), pneumonia (47%), sinusitis (42%), and gastroenteritis (34%). Infections were associated with worsening SMS-related neurobehavioral symptoms. The prevalence of autoimmune and atopic diseases was not increased. Malignancy was not reported. Laboratory evaluation revealed most subjects with SMS to be deficient of isotype-switched memory B cells and many to lack protective antipneumococcal antibodies. SMS antibodies were not more reactive than control antibodies to self-antigens. CONCLUSIONS: Patients with SMS with heterozygous 17p.11.2 deletions display an increased susceptibility to sinopulmonary infections, but not to autoimmune, allergic, or malignant diseases. SMS sera display an antibody reactivity profile favoring neither recognition of pathogen-associated antigens nor self-antigens. Prophylactic strategies to prevent infections may also provide neurobehavioral benefits to selected patients with SMS.


Assuntos
Linfócitos B/imunologia , Síndromes de Imunodeficiência/epidemiologia , Síndrome de Smith-Magenis/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Proteína DEAD-box 58/genética , Feminino , Humanos , Switching de Imunoglobulina , Memória Imunológica , Lactente , Deficiência Intelectual , Masculino , Mutação/genética , Otite , Pneumonia , Prevalência , Sinusite , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/imunologia , Adulto Jovem
13.
Hum Genet ; 136(4): 409-420, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28213671

RESUMO

Smith-Magenis syndrome (SMS), a neurodevelopmental disorder characterized by dysmorphic features, intellectual disability (ID), and sleep disturbances, results from a 17p11.2 microdeletion or a mutation in the RAI1 gene. We performed exome sequencing on 6 patients with SMS-like phenotypes but without chromosomal abnormalities or RAI1 variants. We identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1, and candidate de novo missense variants in an additional two cases. One candidate variant was located in an alpha helix of Necdin (NDN), phased to the paternally inherited allele. NDN is maternally imprinted within the 15q11.2 Prader-Willi Syndrome (PWS) region. This can help clarify NDN's role in the PWS phenotype. No definitive pathogenic gene variants were detected in the remaining SMS-like cases, but we report our findings for future comparison. This study provides information about the inheritance pattern and recurrence risk for patients with identified variants and demonstrates clinical and genetic overlap of neurodevelopmental disorders. Identification and characterization of ID-related genes that assist in development of common developmental pathways and/or gene-networks, may inform disease mechanism and treatment strategies.


Assuntos
Exoma , Síndrome de Smith-Magenis/genética , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Pré-Escolar , Estudos de Coortes , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Masculino , Proteínas Nucleares/genética , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
14.
Am J Med Genet A ; 173(1): 231-238, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27683195

RESUMO

Smith-Magenis syndrome (SMS) is a complex genetic disorder caused by interstitial 17p11.2 deletions encompassing multiple genes, including the retinoic acid induced 1 gene-RAI1-or mutations in RAI1 itself. The clinical spectrum includes developmental delay, cognitive impairment, and behavioral abnormalities, with distinctive physical features that become more evident with age. No patients have been reported to have had offspring. We here describe a girl with developmental delay, mainly compromising the speech area, and her mother with mild intellectual disabilities and minor dysmorphic features. Both had sleep disturbance and attention deficit disorder, but no other atypical behaviors have been reported. In both, CGH-array analysis detected a 15q13.3 interstitial duplication, encompassing CHRNA7. However, the same duplication has been observed in several, apparently healthy, maternal relatives. We, thus, performed a whole exome sequencing analysis, which detected a frameshift mutation in RAI1, de novo in the mother, and transmitted to her daughter. No other family members carried this mutation. This is the first report of an SMS patient having offspring. Our experience confirms the importance of searching for alternative causative genetic mechanisms in case of confounding/inconclusive findings such as a CGH-array result of uncertain significance. © 2016 Wiley Periodicals, Inc.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Mães , Mutação , Núcleo Familiar , Fenótipo , Proteínas Repressoras/genética , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética , Adulto , Criança , Hibridização Genômica Comparativa , Exoma , Facies , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linhagem , Reprodutibilidade dos Testes
15.
Hematology Am Soc Hematol Educ Program ; 2016(1): 137-145, 2016 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-27913472

RESUMO

The advent of novel small-molecule inhibitors has transformed the treatment approaches for patients with chronic lymphocytic leukemia (CLL). These therapies are becoming increasingly used in patients with relapsed disease, patients with 17p deletion, and, as of recently, also in the frontline setting for previously untreated patients with CLL. Moreover, many of these are oral therapies that are significantly less myelosuppressive than chemoimmunotherapy. However, these agents have their own set of unique toxicities with which providers must gain familiarity. There is also ongoing development of second-generation agents which have the promise of less toxicity than the US Food and Drug Administration (FDA)-approved compounds. In addition, immunotherapy and the role of the microenvironment are becoming increasingly important and have therapeutic implications in the treatment of patients with CLL. Ultimately, investigators need to evaluate how to position these and other new exciting therapies and decide on the ultimate role for chemoimmunotherapy in modern times.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Síndrome de Smith-Magenis/terapia , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/imunologia , Aprovação de Drogas , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/imunologia , Microambiente Tumoral/imunologia , Estados Unidos , United States Food and Drug Administration
16.
Hematology Am Soc Hematol Educ Program ; 2016(1): 128-136, 2016 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-27913471

RESUMO

It is an unprecedented time for the treatment of patients with chronic lymphocytic leukemia (CLL) with the recent approval of several targeted agents for use in frontline, relapsed, refractory, and high-risk disease. Traditionally, frontline management of CLL has been a combination of chemotherapy (fludarabine, cyclophosphamide, bendamustine, or chlorambucil) with an anti-CD20 monoclonal antibody (rituximab, ofatumumab, obinutuzumab). The current landscape is rapidly evolving with the advent of therapies that demonstrate selective inhibition of important pathways necessary for CLL proliferation and survival. Despite considerable progress, much is still unknown and optimal treatment selection and sequence is still debatable. None of the new agents have been compared against each other and the impact of adding an additional agent to monotherapy is not yet fully elucidated. In routine clinical practice, the choice of therapy is based on nonrandomized comparisons, presence of comorbidities, and toxicity considerations. These recently approved drugs (ibrutinib, idelalisib, and venetoclax) are reporting excellent outcomes, including patients with high-risk disease such as 17p deletion (17p-) or TP53 mutations (TP53mut). Ibrutinib and venetoclax have been approved for use in 17p- patients (frontline and relapsed, respectively). Ibrutinib is currently moving into the frontline space given recent regulatory approvals. This review will summarize and interpret the limited therapeutic sequencing data available, highlighting the need for additional studies to optimize combination strategies and treatments after failure or discontinuation of these novel agents.


Assuntos
Proliferação de Células/genética , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Síndrome de Smith-Magenis/genética , Proteína Supressora de Tumor p53/genética , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Clorambucila/uso terapêutico , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Ciclofosfamida/uso terapêutico , Análise Mutacional de DNA/métodos , Intervalo Livre de Doença , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Rituximab/uso terapêutico , Síndrome de Smith-Magenis/tratamento farmacológico , Síndrome de Smith-Magenis/mortalidade
17.
Genome Med ; 8(1): 105, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27799067

RESUMO

BACKGROUND: Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors. METHODS: We investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes. RESULTS: Potentially deleterious variants were identified in nine of these individuals using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type, and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of co-expression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1 -/- mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1 -/- mouse model. CONCLUSIONS: These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder.


Assuntos
Exoma/genética , Redes Reguladoras de Genes , Genômica/métodos , Mutação/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/fisiologia , Transcriptoma , Animais , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Epigenomics ; 8(12): 1689-1708, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27855486

RESUMO

Dysregulation of histone methylation has emerged as a major driver of neurodevelopmental disorders including intellectual disabilities and autism spectrum disorders. Histone methyl writer and eraser enzymes generally act within multisubunit complexes rather than in isolation. However, it remains largely elusive how such complexes cooperate to achieve the precise spatiotemporal gene expression in the developing brain. Histone H3K4 methylation (H3K4me) is a chromatin signature associated with active gene-regulatory elements. We review a body of literature that supports a model in which the RAI1-containing H3K4me writer complex counterbalances the LSD1-containing H3K4me eraser complex to ensure normal brain development. This model predicts H3K4me as the nexus of previously unrelated neurodevelopmental disorders.


Assuntos
Encéfalo/metabolismo , Histonas/metabolismo , Anormalidades Múltiplas/genética , Animais , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Ritmo Circadiano/genética , Proteínas Correpressoras/genética , Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/genética , Histona Desmetilases/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Metilação , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas do Tecido Nervoso/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética
19.
Neuron ; 92(2): 392-406, 2016 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-27693255

RESUMO

Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), which is associated with diverse neurodevelopmental and behavioral symptoms as well as obesity. RAI1 encodes a nuclear protein but little is known about its molecular function or the cell types responsible for SMS symptoms. Using genetically engineered mice, we found that Rai1 preferentially occupies DNA regions near active promoters and promotes the expression of a group of genes involved in circuit assembly and neuronal communication. Behavioral analyses demonstrated that pan-neural loss of Rai1 causes deficits in motor function, learning, and food intake. These SMS-like phenotypes are produced by loss of Rai1 function in distinct neuronal types: Rai1 loss in inhibitory neurons or subcortical glutamatergic neurons causes learning deficits, while Rai1 loss in Sim1+ or SF1+ cells causes obesity. By integrating molecular and organismal analyses, our study suggests potential therapeutic avenues for a complex neurodevelopmental disorder.


Assuntos
Comportamento Animal , Regulação da Expressão Gênica/genética , Neurônios/metabolismo , Obesidade/genética , Síndrome de Smith-Magenis/genética , Transativadores/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Variações do Número de Cópias de DNA , Ingestão de Alimentos/genética , Técnicas de Introdução de Genes , Ácido Glutâmico/metabolismo , Haploinsuficiência , Aprendizagem , Camundongos , Camundongos Knockout , Inibição Neural , Fenótipo , Fatores de Processamento de RNA/metabolismo , Proteínas Repressoras/metabolismo
20.
CNS Neurosci Ther ; 22(11): 928-935, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27743421

RESUMO

AIMS: Individuals with Smith-Magenis syndrome (SMS) are reported to have a disrupted circadian rhythm. Our aim was to examine problematic sleeping in those attending our sleep clinic for the first time. METHODS: At intake, caregivers of 50 children and nine adults with SMS were surveyed about the sleep pattern and potential melatonin administration. Sampling of salivary melatonin levels was performed. RESULTS: At intake, exogenous melatonin was used by 16 children (27.1% of sample; 56.3% male) with mean age 6.8 ± 2.8 years, whereas 34 children (57.6%; 7.5 ± 4.8 years old; 64.7% male) and nine adults (15.3%; 36.8 ± 15.3 years old; 44.4% male) were not taking melatonin at intake. Participants were reported to have problems with night waking and early awakenings regardless of melatonin administration. Overall, moderate to high levels of salivary melatonin at noon were found in individuals with SMS. In particular, children with SMS showed a disrupted melatonin pattern. Furthermore, the endogenous melatonin level, age, and gender may potentially interact, yielding the severity range of sleep disturbances reported in SMS. CONCLUSION: Treatment of sleep problems in SMS is complex, and our findings may support person-centered sleep and medication management. Future clinical trials including larger groups may shed light on such approaches.


Assuntos
Ritmo Circadiano/fisiologia , Melatonina/metabolismo , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/diagnóstico , Síndrome de Smith-Magenis/complicações , Adulto , Fatores Etários , Criança , Pré-Escolar , Ingestão de Alimentos , Feminino , Humanos , Masculino , Melatonina/administração & dosagem , Pessoa de Meia-Idade , Radioimunoensaio , Saliva/metabolismo , Síndrome de Smith-Magenis/genética , Adulto Jovem
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