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1.
Int J Pharm Compd ; 24(5): 367-369, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32886633

RESUMO

Congenital ichthyoses are a heterogeneous group of genetic skin disorders characterized by defects in the critical barrier function of the skin. These life-long conditions present a significant therapeutic challenge in dermatology. One important example is Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects, or CHILD syndrome. This is a rare congenital ichthyosis caused by mutations in cholesterol biosynthesis. With limited success, the cutaneous features of this condition have historically been managed symptomatically with emollients, topical keratolytics, and topical steroids. However, over the last decade, topical therapy directed at the pathogenesis of this condition has emerged as an effective treatment. Herein, we report a case of successful treatment of the cutaneous features of CHILD syndrome with compounded simvastatin and cholesterol gel and highlight the role of the compounding pharmacist in the care of patients with congenital ichthyosis.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Colesterol/farmacologia , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Eritrodermia Ictiosiforme Congênita/fisiopatologia , Deformidades Congênitas dos Membros/fisiopatologia , Adolescente , Humanos , Sinvastatina
2.
Am J Hum Genet ; 107(3): 564-574, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32822602

RESUMO

KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.


Assuntos
Atrofia/genética , Doenças Cerebelares/genética , Deficiência Intelectual/genética , Lisina Acetiltransferase 5/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Atrofia/diagnóstico por imagem , Atrofia/fisiopatologia , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/fisiopatologia , Pré-Escolar , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Reparo do DNA/genética , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Heterozigoto , Histonas/genética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto/genética , Processamento de Proteína Pós-Traducional/genética
3.
Cytogenet Genome Res ; 160(3): 124-133, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187602

RESUMO

Trisomy 14 is incompatible with live, but there are several patients reported with mosaic trisomy 14. We aimed to study the pattern of X inactivation and its effect on a translocated autosome and to find out an explanation of the involvement of chromosome 14 in 2 different structural chromosomal abnormalities. We report on a girl with frontal bossing, hypertelorism, low-set ears, micrognathia, cleft palate, congenital heart disease, and abnormal skin pigmentations. The patient displayed iris, choroidal, and retinal coloboma and agenesis of the corpus callosum and cerebellar vermis hypoplasia. Cytogenetic analysis revealed a karyotype 45,X,der(X)t(X;14)(q24;q11)[85]/46,XX,rob(14;14)(q10;q10),+14[35]. Array-CGH for blood and buccal mucosa showed high mosaic trisomy 14 and an Xq deletion. MLPA detected trisomy 14 in blood and buccal mucosa and also showed normal methylation of the imprinting center. FISH analysis confirmed the cell line with trisomy 14 (30%) and demonstrated the mosaic deletion of the Xq subtelomere in both tissues. There was 100% skewed X inactivation for the t(X;14). SNP analysis of the patient showed no region of loss of heterozygosity on chromosome 14. Also, genotype call analysis of the patient and her parents showed heterozygous alleles of chromosome 14 with no evidence of uniparental disomy. Our patient had a severe form of mosaic trisomy 14. We suggest that this cytogenetic unique finding that involved 2 cell lines with structural abnormalities of chromosome 14 occurred in an early postzygotic division. These 2 events may have happened separately or maybe there is a kind of trisomy or monosomy rescue due to dynamic cytogenetic interaction between different cell lines to compensate for gene dosage.


Assuntos
Anormalidades Múltiplas/genética , Trissomia/genética , Inativação do Cromossomo X/genética , Anormalidades Múltiplas/fisiopatologia , Pré-Escolar , Cromossomos Humanos Par 14/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Cariotipagem , Mosaicismo , Fenótipo , Translocação Genética/genética , Trissomia/fisiopatologia
4.
BMC Med Genet ; 21(1): 18, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000717

RESUMO

BACKGROUND: Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance. CASE PRESENTATION: We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03. CONCLUSION: This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Predisposição Genética para Doença , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adulto , Cerebelo/fisiopatologia , Criança , Éxons/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/fisiopatologia , Feminino , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mutação/genética , Linhagem , Isoformas de Proteínas/genética , Retina/metabolismo , Retina/patologia , Retina/fisiopatologia , Vietnã , Sequenciamento Completo do Exoma
5.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165742, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105826

RESUMO

Transforming growth factor beta-activated kinase 1 (TAK1) is a highly conserved kinase protein encoded by MAP3K7, and activated by multiple extracellular stimuli, growth factors and cytokines. Heterozygous variants in MAP3K7 cause the cardiospondylocarpofacial syndrome (CSCFS) which is characterized by short stature, dysmorphic facial features, cardiac septal defects with valve dysplasia, and skeletal anomalies. CSCFS has been described in seven patients to date and its molecular pathogenesis is only partially understood. Here, the functional effects of the MAP3K7 c.737-7A > G variant, previously identified in a girl with CSCFS and additional soft connective tissue features, were explored. This splice variant generates an in-frame insertion of 2 amino acid residues in the kinase domain of TAK1. Computational analysis revealed that this in-frame insertion alters protein dynamics in the kinase activation loop responsible for TAK1 autophosphorylation after binding with its interactor TAB1. Co-immunoprecipitation studies demonstrate that the ectopic expression of TAK1-mutated protein impairs its ability to physically bind TAB1. In patient's fibroblasts, MAP3K7 c.737-7A > G variant results in reduced TAK1 autophosphorylation and dysregulation of the downstream TAK1-dependent signaling pathway. TAK1 loss-of-function is associated with an impaired TGFß-mediated α-SMA cytoskeleton assembly and cell migration, and defective autophagy process. These findings contribute to our understanding of the molecular pathogenesis of CSCFS and might offer the rationale for the design of novel therapeutic targets.


Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Autofagia/genética , Perda Auditiva Bilateral/genética , MAP Quinase Quinase Quinases/genética , Insuficiência da Valva Mitral/genética , Osteosclerose/genética , Anormalidades Múltiplas/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Criança , Citoesqueleto/genética , Feminino , Fibroblastos/metabolismo , Perda Auditiva Bilateral/fisiopatologia , Humanos , Mutação com Perda de Função/genética , Insuficiência da Valva Mitral/fisiopatologia , Mutação/genética , Osteosclerose/fisiopatologia , Fosforilação/genética , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica/genética , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/genética
6.
Clin Dysmorphol ; 29(1): 10-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31577543

RESUMO

With the increasing availability and clinical use of exome and whole-genome sequencing, reverse phenotyping is now becoming common practice in clinical genetics. Here, we report a patient identified through the Wellcome Trust Deciphering Developmental Disorders study who has homozygous pathogenic variants in CC2D2A and a de-novo heterozygous pathogenic variant in KIDINS220. He presents with developmental delay, intellectual disability, and oculomotor apraxia. Reverse phenotyping has demonstrated that he likely has a composite phenotype with contributions from both variants. The patient is much more mildly affected than those with Joubert Syndrome or Spastic paraplegia, intellectual disability, nystagmus, and obesity, the conditions associated with CC2D2A and KIDINS220 respectively, and therefore, contributes to the phenotypic variability associated with the two conditions.


Assuntos
Anormalidades Múltiplas , Cerebelo/anormalidades , Proteínas do Citoesqueleto/genética , Deficiências do Desenvolvimento , Anormalidades do Olho , Deficiência Intelectual , Doenças Renais Císticas , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Cerebelo/patologia , Cerebelo/fisiopatologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/fisiopatologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/fisiopatologia , Homozigoto , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Doenças Renais Císticas/fisiopatologia , Masculino , Retina/patologia , Retina/fisiopatologia
7.
J Hum Genet ; 64(11): 1133-1136, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31481716

RESUMO

Cyclophilins are a type of peptidyl-prolyl cis-trans isomerases. CWC27, one of the known human cyclophilins, is recruited by the spliceosome for the pre-mRNA splicing process. Biallelic deleterious variants in CWC27 lead to a spectrum of overlapping phenotypes including retinal degeneration, skeletal anomalies, short stature, and neurological defects. The present work reports a woman showing these clinical features, in addition to hypergonadotropic hypogonadism, hypoplastic/agenesic teeth, and cataracts, not previously associated with such phenotypic spectrum. Whole exome sequencing on this patient identified a novel CWC27 homozygous variant predicted to originate a severely truncated protein and the consequent loss of functionality. The clinical and genetic characterization of such patient could provide further insight into the underlying causes of the spliceosomopathies.


Assuntos
Anormalidades Múltiplas/genética , Ciclofilinas/genética , Sequenciamento Completo do Exoma , Anormalidades Múltiplas/fisiopatologia , Nanismo/genética , Nanismo/fisiopatologia , Feminino , Humanos , Lactente , Fenótipo , Processamento de RNA/genética , Degeneração Retiniana/genética , Degeneração Retiniana/fisiopatologia , Esqueleto/anormalidades , Esqueleto/fisiopatologia
8.
J Hum Genet ; 64(11): 1067-1073, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31427716

RESUMO

Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a rare and severe disorder characterized by functional obstruction in the urinary and gastrointestinal tract. The molecular basis of this condition has been defined recently. Heterozygous variants in ACTG2, homozygous mutations in LMOD1, MYLK, and MYH9 were related to the pathogenesis of the syndrome, which encodes proteins involved in the process of smooth muscle contraction, supporting a myopathic basis for the disease. Recent studies have identified homozygous or compound heterozygous variants in MYH11 as a candidate gene of MMIHS. In this report, we described a nonconsanguineous Chinese family with three male fetuses affected with megacystis. Trio-targeted exome sequencing identified compound heterozygous variants, c.2051 G > A (p.R684H) and c.3540_3541delinsTT (p.(E1180D, Q1181Ter)), in MYH11 (NM_001040114). The variants were inherited from the parents, respectively. Western blotting showed a marked decrease in MYH11 protein in the proband's umbilical cord tissue compared with the control sample. The study's results confirmed that MYH11 is a candidate gene for MMIHS with autosomal recessive (AR) inheritance and expanded the mutation spectrum for this clinical condition. Combining clinical phenotype with molecular diagnosis may enable the identification of candidate genes for potential monogenic diseases and facilitate accurate genetic counseling, informed decision-making, and prenatal diagnosis.


Assuntos
Anormalidades Múltiplas/genética , Colo/anormalidades , Genes Recessivos , Predisposição Genética para Doença , Pseudo-Obstrução Intestinal/genética , Cadeias Pesadas de Miosina/genética , Bexiga Urinária/anormalidades , Anormalidades Múltiplas/fisiopatologia , Colo/fisiopatologia , Feminino , Feto , Trato Gastrointestinal/patologia , Heterozigoto , Humanos , Pseudo-Obstrução Intestinal/fisiopatologia , Masculino , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Bexiga Urinária/fisiopatologia , Sistema Urinário/patologia , Sequenciamento Completo do Exoma
9.
BMC Pulm Med ; 19(1): 163, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462237

RESUMO

BACKGROUND: Ablepharon macrostomia syndrome (AMS) is a rare congenital malformation disorder caused by the autosomal-dominant mutations in gene TWIST2. Patients affected by the disease present abnormalities in ectoderm-derived structures mainly consisting in major facial dysmorphic features and rarely in visceral anomalies. The only laryngo-tracheal defect reported is malacia, with no reference to any anatomical stenosis. We describe a unique case of laryngo-tracheal stenosis in a woman, with genetically confirmed AMS currently followed at our Department. CASE PRESENTATION: A 37-year-old Caucasian woman was admitted to the intensive care unit for acute dyspnea that required orotracheal intubation followed by tracheostomy. The bronchoscopy revealed abnormal tracheal tissue at the level of the cricoid and the first three tracheal rings reducing airway caliber by 80% (grade III according to the Cotton-Meyer classification). Treatment of the stenosis by means of temporary tracheostomy and corticosteroids therapy resulted in airway patency restoration and patient's return to her normal activities. Bronchoscopy at four and five months showed disappearance of the abnormal tissue and a residual anatomical laryngo-tracheal stenosis of about 20% (grade I according to the Cotton-Meyer classification) of the normal airway caliber. CONCLUSIONS: To our knowledge, this is the first patient affected by AMS presenting with laryngo-tracheal stenosis.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/fisiopatologia , Macrostomia/diagnóstico , Macrostomia/fisiopatologia , Traqueia/cirurgia , Estenose Traqueal/terapia , Corticosteroides/uso terapêutico , Adulto , Dispneia/etiologia , Feminino , Humanos , Intubação Intratraqueal , Mutação , Estenose Traqueal/etiologia , Traqueostomia
10.
Neonatal Netw ; 38(2): 63-68, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31470368

RESUMO

Numerous chromosome abnormalities are seen in NICUs around the world. With increased access to health care, in some cases, parents and practitioners are aware of an abnormality prior to birth, and a plan of care can be made. However, in many situations there is no prenatal diagnosis and these discoveries and diagnoses are made during the neonate's NICU stay. Providers in the NICU setting need to have a vast understanding of chromosome abnormalities, as they may be the first to guide parents through the maze of decisions that will follow. This case study analyzes a very rare deletion on chromosome 1q43q44. The 1q43q44 deletion is located at the subtelomeric region, the region farthest from the centromere, on the long arm of chromosome 1. This case study describes Baby D, who presented with multiple anomalies and was subsequently diagnosed with 1q43q44 deletion.


Assuntos
Anormalidades Múltiplas , Deleção Cromossômica , Testes Genéticos/métodos , Deficiência Intelectual , Enfermagem Neonatal/métodos , Triagem Neonatal/métodos , Pais , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adulto , Assistência ao Convalescente/métodos , Cromossomos Humanos Par 1 , Feminino , Humanos , Recém-Nascido , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Unidades de Terapia Intensiva Neonatal , Trabalho de Parto Induzido/métodos , Exame Neurológico/métodos , Pais/educação , Pais/psicologia , Gravidez , Apoio Social , Avaliação de Sintomas/métodos
11.
Taiwan J Obstet Gynecol ; 58(4): 531-535, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31307746

RESUMO

OBJECTIVE: We purposed to review prenatal diagnoses of ureterocele, to determine the sonographic findings and additional abnormalities, and to illustrate the pregnancy outcomes of these patients. MATERIAL AND METHODS: We reviewed the records of 24 patients with the diagnosis of ureterocele in our referral center between January 2010-March 2017. Prenatal sonographic findings, antenatal course, and postnatal follow-up were obtained. RESULTS: The mean gestational age at first US diagnosis was 24.5 ± 2.9 weeks. 13 (54.1%) of fetuses were female, and 11 (45.9%) were male. Ureterocele was associated with the duplex kidney in 17 (70.8%), MCDK in 5 (20.8%) and hydronephrosis with a single system in 1 (4.2%) and pelvic kidney in 1 (4.2%) fetuses. Postnatal follow-up was achieved in 22 of 24 (91.6%) cases, and mean follow-up interval was 56 ± 14.2. Months. The diagnosis of ureterocele was confirmed in 22 (91.6%) cases postnatally. 15 of 22 (68%) cases were classified as extravesical ureterocele, and 7 (32%) cases were intravesical ureterocele. Postnatal confirmation of duplex kidney achieved in 16 of 17 (94.1%) patients. 17 (77.2%) patients were required surgical intervention, and 5 (22.8%) cases were managed conservatively. 15 of 16 (93.7%) cases who were diagnosed duplex kidney underwent surgery however 2 of 5 (40%) cases which were confirmed MCDK required an operation. Cystoscopic ureterocele incision was the initial approach for the surgical management and performed all of the cases which required surgery. It was curative in 10 of 17 (58.8%) patients and 7 (41.2%) cases needed to further operations. Ureteroselectomy and common-sheath ureteroneocystostomy was performed in 5 (29.1%) cases and. 2 (%11.7%) cases underwent partial nephrectomy. CONCLUSION: Ureterocele can be accurately diagnosed by prenatal sonography, and it is a significant clue for the diagnosis of a duplex kidney. Postnatal prognosis depends on associated anomaly and presence of reflux and upper pole function.


Assuntos
Idade Gestacional , Rim Displásico Multicístico/diagnóstico por imagem , Ultrassonografia Pré-Natal , Ureterocele/diagnóstico por imagem , Ureterocele/fisiopatologia , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Rim Displásico Multicístico/epidemiologia , Rim Displásico Multicístico/fisiopatologia , Cuidado Pós-Natal/métodos , Diagnóstico Pré-Natal/métodos , Prognóstico , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Turquia , Ureterocele/congênito
12.
BMJ Case Rep ; 12(5)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068350

RESUMO

Multiple pterygium syndrome of lethal type is a very rare genetic condition affecting the skin, muscles and skeleton. It is characterised by minor facial abnormalities, prenatal growth deficiency, spine defects, joint contractures, and webbing (pterygia) of the neck, elbows, back of the knees, armpits and fingers. We present a case of lethal multiple pterygium syndrome born at our hospital proven by the genetic analysis showing a double homozygous mutation.


Assuntos
Anormalidades Múltiplas/genética , Hipertermia Maligna/diagnóstico , Hipertermia Maligna/genética , Metaloendopeptidases/genética , Mutação , Receptores Nicotínicos/genética , Anormalidades da Pele/diagnóstico , Anormalidades da Pele/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Consanguinidade , Análise Mutacional de DNA , Suscetibilidade a Doenças , Evolução Fatal , Aconselhamento Genético , Heterogeneidade Genética , Humanos , Recém-Nascido , Masculino , Hipertermia Maligna/fisiopatologia , Linhagem , Anormalidades da Pele/fisiopatologia
15.
Int J Mol Sci ; 20(5)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836598

RESUMO

Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients; one at 16p12.2 was found in four patients; two close SROs at 16p11.2 were found in twelve patients; finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Anormalidades Múltiplas/classificação , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/classificação , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Recombinação Homóloga/genética , Humanos , Lactente , Recém-Nascido , Cariótipo , Masculino , Fenótipo , Duplicações Segmentares Genômicas/genética , Adulto Jovem
16.
Bol Med Hosp Infant Mex ; 76(2): 100-103, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30907385

RESUMO

Background: Ring chromosome 13 is an infrequent cytogenetic disorder clinically characterized by growth and psychomotor development retardation, cognitive deficit, microcephaly, facial dysmorphism, genital alterations and thumb hypoplasia. Case report: A 8-month-old patient was evaluated for presenting short stature, psychomotor development delay, microcephaly, facial dysmorphism, penoscrotal hypospadias and thumb hypoplasia. Lissencephaly, neuroconductive hearing loss on the right side and small ostium secundum interatrial communication were evident. The cytogenetic study of the patient showed 46, XY, r (13) in 30 cells analyzed. Conclusions: Clinical findings that can guide the diagnosis of this infrequent structural chromosomal alteration are highlighted, as well as the interdisciplinary medical evaluation required and adequate family genetic counseling.


Assuntos
Anormalidades Múltiplas/diagnóstico , Transtornos Cromossômicos/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Cromossomos Humanos Par 13/genética , Humanos , Lactente , Masculino , Cromossomos em Anel
17.
J Hum Genet ; 64(6): 561-572, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30858506

RESUMO

Variants have been identified in the embryonic ectoderm development (EED) gene in seven patients with syndromic overgrowth similar to that observed in Weaver syndrome. Here, we present three additional patients with missense variants in the EED gene. All the missense variants reported to date (including the three presented here) have localized to one of seven WD40 domains of the EED protein, which are necessary for interaction with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). In addition, among the seven patients reported in the literature and the three new patients presented here, all of the reported pathogenic variants except one occurred at one of four amino acid residues in the EED protein. The recurrence of pathogenic variation at these loci suggests that these residues are functionally important (mutation hotspots). In silico modeling and calculations of the free energy changes resulting from these variants suggested that they not only destabilize the EED protein structure but also adversely affect interactions between EED, EZH2, and/or H3K27me3. These cases help demonstrate the mechanism(s) by which apparently deleterious variants in the EED gene might cause overgrowth and lend further support that amino acid residues in the WD40 domain region may be mutation hotspots.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Deformidades Congênitas da Mão/genética , Histona-Lisina N-Metiltransferase/genética , Complexo Repressor Polycomb 2/genética , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Simulação por Computador , Hipotireoidismo Congênito/etiologia , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/etiologia , Anormalidades Craniofaciais/fisiopatologia , Proteína Potenciadora do Homólogo 2 de Zeste/química , Feminino , Deformidades Congênitas da Mão/etiologia , Deformidades Congênitas da Mão/fisiopatologia , Histona-Lisina N-Metiltransferase/química , Humanos , Masculino , Simulação de Dinâmica Molecular , Taxa de Mutação , Mutação de Sentido Incorreto/genética , Complexo Repressor Polycomb 2/química , Conformação Proteica , Repetições WD40/genética , Sequenciamento Completo do Exoma
19.
Genes Brain Behav ; 18(8): e12568, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30891914

RESUMO

The recessive mutant mice bate palmas (bapa) - claps in Portuguese arose from N-ethyl-N-nitrosourea mutagenesis. A single nucleotide, T > C, change in exon 13, leading to a Thr1289 Ala substitution, was identified in the lysine (K)-specific methyltransferase 2D gene (Kmt2d) located on chromosome 15. Mutations with a loss-of-function in the KMT2D gene on chromosome 12 in humans are responsible for Kabuki syndrome (KS). Phenotypic characterization of the bapa mutant was performed using a behavioral test battery to evaluate the parameters related to general activity, the sensory nervous system, the psychomotor system, and the autonomous nervous system, as well as to measure motor function and spatial memory. Relative to BALB/cJ mice, the bapa mutant showed sensory and psychomotor impairments, such as hypotonia denoted by a surface righting reflex impairment and hindquarter fall, and a reduction in the auricular reflex, suggesting hearing impairment. Additionally, the enhanced general activity showed by the increased rearing and grooming frequency, distance traveled and average speed possibly presupposes the presence of hyperactivity of bapa mice compared with the control group. A slight motor coordination dysfunction was showed in bapa mice, which had a longer crossing time on the balance beam compared with BALB/cJ controls. Male bapa mice also showed spatial gait pattern changes, such as a shorter stride length and shorter step length. In conclusion, the bapa mouse may be a valuable animal model to study the mechanisms involved in psychomotor and behavior impairments, such as hypotonia, fine motor coordination and hyperactivity linked to the Kmt2d mutation.


Assuntos
Anormalidades Múltiplas/genética , Comportamento Animal , Face/anormalidades , Doenças Hematológicas/genética , Histona-Lisina N-Metiltransferase/genética , Mutação com Perda de Função , Proteína de Leucina Linfoide-Mieloide/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/fisiopatologia , Animais , Modelos Animais de Doenças , Face/fisiopatologia , Marcha , Audição , Doenças Hematológicas/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Movimento , Hipotonia Muscular/genética , Reflexo , Doenças Vestibulares/fisiopatologia
20.
Cell Mol Gastroenterol Hepatol ; 7(2): 411-431, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30739867

RESUMO

BACKGROUND & AIMS: A generalized human pacemaking syndrome, chronic atrial and intestinal dysrhythmia (CAID) (OMIM 616201), is caused by a homozygous SGO1 mutation (K23E), leading to chronic intestinal pseudo-obstruction and arrhythmias. Because CAID patients do not show phenotypes consistent with perturbation of known roles of SGO1, we hypothesized that noncanonical roles of SGO1 drive the clinical manifestations observed. METHODS: To identify a molecular signature for CAID syndrome, we achieved unbiased screens in cell lines and gut tissues from CAID patients vs wild-type controls. We performed RNA sequencing along with stable isotope labeling with amino acids in cell culture. In addition, we determined the genome-wide DNA methylation and chromatin accessibility signatures using reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing. Functional studies included patch-clamp, quantitation of transforming growth factor-ß (TGF-ß) signaling, and immunohistochemistry in CAID patient gut biopsy specimens. RESULTS: Proteome and transcriptome studies converge on cell-cycle regulation, cardiac conduction, and smooth muscle regulation as drivers of CAID syndrome. Specifically, the inward rectifier current, an important regulator of cellular function, was disrupted. Immunohistochemistry confirmed overexpression of Budding Uninhibited By Benzimidazoles 1 (BUB1) in patients, implicating the TGF-ß pathway in CAID pathogenesis. Canonical TGF-ß signaling was up-regulated and uncoupled from noncanonical signaling in CAID patients. Reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing experiments showed significant changes of chromatin states in CAID, pointing to epigenetic regulation as a possible pathologic mechanism. CONCLUSIONS: Our findings point to impaired inward rectifier potassium current, dysregulation of canonical TGF-ß signaling, and epigenetic regulation as potential drivers of intestinal and cardiac manifestations of CAID syndrome. Transcript profiling and genomics data are as follows: repository URL: https://www.ncbi.nlm.nih.gov/geo; SuperSeries GSE110612 was composed of the following subseries: GSE110309, GSE110576, and GSE110601.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/metabolismo , Epigenômica , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Adulto , Metilação de DNA/genética , Derme/patologia , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Canais de Potássio/metabolismo , Proteoma/metabolismo , Reprodutibilidade dos Testes , Síndrome
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