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2.
Medicine (Baltimore) ; 99(38): e22300, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957390

RESUMO

INTRODUCTION: Bardet-Biedl syndrome, which compromises airway management and the cardiovascular and renal systems, is a rare ciliopathic syndrome characterized by multisystem involvement and varying genetic etiologies and clinical manifestations. PATIENT CONCERNS: A 13-year-old female patient had a history of chronic renal failure, hypothyroidism, mental retardation, hypogonadotropic hypogonadism, obesity, and retinitis pigmentosa and was undergoing 4-hour hemodialysis 3 days a week. DIAGNOSIS: We diagnosed Bardet-Biedl syndrome based on the results of genetic tests. INTERVENTIONS: We performed renal transplantation under general anesthesia while considering the perioperative risks of airway obstruction and hypothermia. OUTCOMES: Multidisciplinary preoperative evaluation is crucial to avoid perioperative complications. The risk of an obstructed airway should be considered. Hypothyroidism is a rare consequence of Bardet-Biedl syndrome. Rocuronium and sugammadex are safe for anesthetic management during renal transplantation to address Bardet-Biedl syndrome. CONCLUSION: Safe anesthetic management can be achieved with the rigorous preoperative assessment of perioperative complications.


Assuntos
Anestesia Geral/métodos , Síndrome de Bardet-Biedl/complicações , Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Anormalidades Múltiplas/etiologia , Adolescente , Feminino , Humanos , Falência Renal Crônica/diagnóstico por imagem , Falência Renal Crônica/etiologia , Cuidados Pré-Operatórios
3.
Medicine (Baltimore) ; 99(35): e21758, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871896

RESUMO

INTRODUCTION: Gastroesophageal reflux disease is a common and troublesome condition. This paper reports a rare case of gastroesophageal reflux disease caused by ectopic biliary drainage accompanying the absence of a pyloric channel and duodenal bulb in a female patient with multiple underlying malformations. PATIENT CONCERNS: A 24-year-old female presented with acid regurgitation and abdominal pain for one month. She was born two weeks premature and with blindness of the right eye. Cardiac murmur was detected in the physical examination. DIAGNOSIS: Gastroendoscopy was performed, and a class D reflux esophagitis and ectopic papilla complicated with the absence of a pyloric channel and duodenal bulb were found. Doppler echocardiography further confirmed the defects of atrial and ventricular septa. Trio-based whole exome sequencing was performed on the proband and her family to find the potential association of multiple variations. However, no putative pathogenic mutations were found. INTERVENTIONS: The patient received proton pump inhibitors and prokinetic treatment and underwent surgical repair of septal defects. OUTCOMES: The symptoms were quickly relieved, and the patient was kept stable upon follow-up. CONCLUSION: The combination of an absent pylorus and ectopic papilla is a rare cause of reflux esophagitis. Unusual gastrointestinal anatomical variations may be accompanied by other malformations. Though no remarkable mutation were detected in this case, sequencing is an efficient technique worth full consideration.


Assuntos
Ampola Hepatopancreática/anormalidades , Esofagite Péptica/etiologia , Anormalidades Múltiplas , Cegueira/congênito , Esofagite Péptica/tratamento farmacológico , Feminino , Gastroscopia , Comunicação Interatrial/diagnóstico por imagem , Comunicação Interatrial/cirurgia , Comunicação Interventricular/diagnóstico por imagem , Comunicação Interventricular/cirurgia , Humanos , Inibidores da Bomba de Prótons/uso terapêutico , Sequenciamento Completo do Exoma , Adulto Jovem
4.
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
5.
Nat Commun ; 11(1): 4673, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938917

RESUMO

RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation. Germline mutation of RAS-MAPK genes lead to the Noonan-spectrum of syndromes. Here, we present a patient affected by a 6p-interstitial microdeletion with unknown underlying molecular etiology. Examination of 6p-interstitial microdeletion cases reveals shared clinical features consistent with Noonan-spectrum disorders including short stature, facial dysmorphia and cardiovascular abnormalities. We find the RAS-responsive element binding protein-1 (RREB1) is the common deleted gene in multiple 6p-interstitial microdeletion cases. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy phenocopying the human syndrome. Rreb1 haploinsufficiency leads to sensitization of MAPK signaling. Rreb1 recruits Sin3a and Kdm1a to control H3K4 methylation at MAPK pathway gene promoters. Haploinsufficiency of SIN3A and mutations in KDM1A cause syndromes similar to RREB1 haploinsufficiency suggesting genetic perturbation of the RREB1-SIN3A-KDM1A complex represents a new category of RASopathy-like syndromes arising through epigenetic reprogramming of MAPK pathway genes.


Assuntos
Proteínas de Ligação a DNA/genética , Haploinsuficiência , Sistema de Sinalização das MAP Quinases/genética , Síndrome de Noonan/etiologia , Fatores de Transcrição/genética , Proteínas ras/metabolismo , Anormalidades Múltiplas/genética , Animais , Deleção Cromossômica , Cromossomos Humanos Par 6 , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Masculino , Metilação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexo Correpressor Histona Desacetilase e Sin3/genética , Complexo Correpressor Histona Desacetilase e Sin3/metabolismo , Fatores de Transcrição/metabolismo , Proteínas ras/genética
7.
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
8.
Nat Commun ; 11(1): 4287, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855419

RESUMO

Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.


Assuntos
Anormalidades Múltiplas/etiologia , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Quadruplex G , Troca de Cromátide Irmã , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Proliferação de Células , RNA Helicases DEAD-box/química , DNA Helicases/química , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Estabilidade Proteica , Pseudogenes , RNA Helicases/genética , RNA Helicases/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Síndrome , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
9.
Rinsho Shinkeigaku ; 60(9): 609-613, 2020 Sep 29.
Artigo em Japonês | MEDLINE | ID: mdl-32779596

RESUMO

A 23-year-old man admitted to our hospital with headache and dysarthria. Head MRI showed multiple acute cerebral infarctions in the right posterior circulation. Atlantoaxial dislocation, atlas dysplasia and thrombotic occlusion of right vertebral artery (VA), and blood flow disruption due to cervical rotation was observed. The axial dental process bordered to the right VA, and repeated contact stimulation by cervical rotation may cause intimal damage resulting in thrombotic occlusion. In this case, various systemic malformations such as atrial septal defect, atlas posterior arch hypoplasia, bovine left common carotid bifurcation malformation, double inferior vena cava and horseshoe kidney may have been congenital syndromes. Atlantoaxial dislocation may be an important and under-recognized cause of stroke in young adults.


Assuntos
Anormalidades Múltiplas , Arteriopatias Oclusivas/etiologia , Articulação Atlantoaxial , Doenças do Desenvolvimento Ósseo/complicações , Infarto Cerebral/etiologia , Atlas Cervical , Luxações Articulares/complicações , Pescoço/fisiologia , Rotação , Trombose/etiologia , Artéria Vertebral , Adulto , Arteriopatias Oclusivas/diagnóstico por imagem , Articulação Atlantoaxial/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Infarto Cerebral/diagnóstico por imagem , Atlas Cervical/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Humanos , Imageamento Tridimensional , Luxações Articulares/diagnóstico por imagem , Masculino , Síndrome , Trombose/diagnóstico por imagem , Adulto Jovem
10.
Am J Hum Genet ; 107(3): 514-526, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32791035

RESUMO

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. Although recent studies have revealed several MMAF-associated genes and demonstrated MMAF to be a genetically heterogeneous disease, at least one-third of the cases are still not well understood for their etiology. Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men. Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes. Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. CFAP58 is predominantly expressed in the testis and encodes a cilia- and flagella-associated protein. Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece. Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants. We generated Cfap58-knockout mice via CRISPR/Cas9 technology. The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men. Overall, our findings in humans and mice strongly suggest that CFAP58 plays a vital role in sperm flagellogenesis and demonstrate that bi-allelic loss-of-function variants in CFAP58 can cause axoneme and peri-axoneme malformations leading to male infertility. This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia.


Assuntos
Anormalidades Múltiplas/genética , Astenozoospermia/genética , Axonema/genética , Infertilidade Masculina/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Anormalidades Múltiplas/patologia , Alelos , Animais , Astenozoospermia/fisiopatologia , Axonema/patologia , Sistemas CRISPR-Cas/genética , Proteínas de Ciclo Celular/genética , Homozigoto , Humanos , Infertilidade Masculina/patologia , Mutação com Perda de Função/genética , Perda de Heterozigosidade/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas dos Microtúbulos/genética , Mitocôndrias/genética , Cauda do Espermatozoide/metabolismo , Cauda do Espermatozoide/patologia , Testículo/metabolismo , Testículo/patologia , Sequenciamento Completo do Exoma
11.
Medicine (Baltimore) ; 99(29): e20574, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702813

RESUMO

RATIONALE: Schaaf-Yang syndrome, a rare imprinted hereditary disease caused by MAGEL2 variants, manifests as developmental delay/intellectual disability, neonatal hypotonia, feeding difficulties, contractures, and autism spectrum disorder. PATIENT CONCERNS: Patient 1 and 2 were infant girls presenting facial dysmorphisms, contractures of interphalangeal joints, neonatal hypotonia, feeding difficulties, congenital heart diseases, and respiratory complications. Besides, Patient 2 presented with delayed psychomotor development. DIAGNOSIS: Whole-exome sequencing was performed and heterozygous mutations of the MAGEL2 gene were detected in the patients. They were diagnosed as Schaaf-Yang syndrome. INTERVENTIONS: The patients received supportive treatment including mechanical ventilation, parenteral nutrition and gastric tube feeding. OUTCOMES: Whole-exome sequencing revealed de novo heterozygous c.1996dupC pathogenic mutations in the MAGEL2 gene in the 2 patients. They died due to respiratory failure at the age of 20 days and 98 days, respectively. LESSONS: Our results indicate that MAGEL2 variants can cause congenital heart disease and fatal respiratory complications, broadening the phenotypic spectrum and adding to the fatal cases of Schaaf-Yang syndrome. We highly suggest that the MAGEL2 gene should be added to gene-panels or gene-filters in next-generation sequencing-based diagnostics, which is of great significance for early diagnosis and early intervention of Schaaf-Yang syndrome patients.


Assuntos
Anormalidades Múltiplas/genética , Testes Genéticos/métodos , Proteínas/genética , Sequenciamento Completo do Exoma/métodos , Criança , Contratura/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Evolução Fatal , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Feminino , Articulações dos Dedos/fisiopatologia , Cardiopatias Congênitas/genética , Humanos , Lactente , Recém-Nascido , Masculino , Hipotonia Muscular/genética , Atrofia Muscular/genética , Cuidados Paliativos , Insuficiência Respiratória/genética , Síndrome
12.
Medicine (Baltimore) ; 99(28): e21114, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664135

RESUMO

RATIONALE: Cervical chondrocutaneous branchial remnants are rare, benign, congenital anomalies, frequently seen bilaterally. PATIENT CONCERNS: Here, we report the case of a 4-month-old female infant who presented with bilateral lower neck skin tag since birth. DIAGNOSIS AND INTERVENTIONS: The patient underwent mass excision. The final pathological diagnosis was bilateral cervical chondrocutaneous branchial remnants with hyaline cartilage. OUTCOMES: No complications were observed after excision. One-year follow-up revealed no recurrence. LESSONS: Bilateral chondrocutaneous branchial remnants are rare anomalies. They are often associated with cardiac or genitourinary abnormalities. Therefore, additional preoperative imaging of the abdomen and heart are recommended.


Assuntos
Anormalidades Múltiplas , Região Branquial/anormalidades , Cartilagem/anormalidades , Coristoma/diagnóstico , Pescoço/anormalidades , Anormalidades da Pele/diagnóstico , Biópsia , Feminino , Humanos , Lactente
13.
Am J Hum Genet ; 107(2): 330-341, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32619401

RESUMO

Sperm malformation is a direct factor for male infertility. Multiple morphological abnormalities of the flagella (MMAF), a severe form of asthenoteratozoospermia, are characterized by immotile spermatozoa with malformed and/or absent flagella in the ejaculate. Previous studies indicated genetic heterogeneity in MMAF. To further define genetic factors underlying MMAF, we performed whole-exome sequencing in a cohort of 90 Chinese MMAF-affected men. Two cases (2.2%) were identified as carrying bi-allelic missense DNAH8 variants, variants which were either absent or rare in the control human population and were predicted to be deleterious by multiple bioinformatic tools. Re-analysis of exome data from a second cohort of 167 MMAF-affected men from France, Iran, and North Africa permitted the identification of an additional male carrying a DNAH8 homozygous frameshift variant. DNAH8 encodes a dynein axonemal heavy-chain component that is expressed preferentially in the testis. Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring bi-allelic DNAH8 variants showed a highly aberrant morphology and ultrastructure of the sperm flagella. Immunofluorescence assays performed on the spermatozoa from men harboring bi-allelic DNAH8 variants revealed the absent or markedly reduced staining of DNAH8 and its associated protein DNAH17. Dnah8-knockout male mice also presented typical MMAF phenotypes and sterility. Interestingly, intracytoplasmic sperm injections using the spermatozoa from Dnah8-knockout male mice resulted in good pregnancy outcomes. Collectively, our experimental observations from humans and mice demonstrate that DNAH8 is essential for sperm flagellar formation and that bi-allelic deleterious DNAH8 variants lead to male infertility with MMAF.


Assuntos
Anormalidades Múltiplas/genética , Dineínas do Axonema/genética , Flagelos/genética , Variação Genética/genética , Infertilidade Masculina/genética , Cauda do Espermatozoide/patologia , Alelos , Animais , Estudos de Coortes , Exoma/genética , Feminino , Homozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Espermatozoides/anormalidades , Testículo/anormalidades , Sequenciamento Completo do Exoma/métodos
14.
Nat Commun ; 11(1): 3168, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576830

RESUMO

In humans, mutations in the PIEZO2 gene, which encodes for a mechanosensitive ion channel, were found to result in skeletal abnormalities including scoliosis and hip dysplasia. Here, we show in mice that loss of Piezo2 expression in the proprioceptive system recapitulates several human skeletal abnormalities. While loss of Piezo2 in chondrogenic or osteogenic lineages does not lead to human-like skeletal abnormalities, its loss in proprioceptive neurons leads to spine malalignment and hip dysplasia. To validate the non-autonomous role of proprioception in hip joint morphogenesis, we studied this process in mice mutant for proprioceptive system regulators Runx3 or Egr3. Loss of Runx3 in the peripheral nervous system, but not in skeletal lineages, leads to similar joint abnormalities, as does Egr3 loss of function. These findings expand the range of known regulatory roles of the proprioception system on the skeleton and provide a central component of the underlying molecular mechanism, namely Piezo2.


Assuntos
Canais Iônicos/metabolismo , Anormalidades Musculoesqueléticas/metabolismo , Sistema Musculoesquelético/metabolismo , Neurônios/metabolismo , Propriocepção/fisiologia , Anormalidades Múltiplas , Animais , Remodelação Óssea , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Proteína 3 de Resposta de Crescimento Precoce/metabolismo , Predisposição Genética para Doença/genética , Luxação do Quadril/genética , Luxação do Quadril/metabolismo , Luxação do Quadril/patologia , Articulação do Quadril/anatomia & histologia , Articulação do Quadril/metabolismo , Articulação do Quadril/patologia , Canais Iônicos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/patologia , Sistema Musculoesquelético/patologia , Escoliose
15.
Tunis Med ; 98(5): 420-422, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32548846

RESUMO

Cystic Fibrosis (CF) is a lethal autosomal recessive condition due to a defect at the level of the transmembrane conductance regulator gene which plays a role in cell homeostasis. Numerous mutations have been identified as the cause of this gene defect, with delF508 being one of the most common mutations in Tunisia. This is a case report describing, up to our knowledge, the second case of a patient with CF carrying a rare mutation: W19X. W19X is a nonsense mutation that has been previously identified in only one other Tunisian patient with CF. Since both incidence of this mutation have been described in Tunisia, it seems as if W19X is specific to Tunisian CF patient with significant morbidities. The information provided by this study contributes to defining the molecular spectrum of CF in Tunisia, in the aim of improving genetic testing and prenatal diagnosis.


Assuntos
Códon sem Sentido , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Fibrose Cística/diagnóstico , Fibrose Cística/patologia , Frequência do Gene , Testes Genéticos , Humanos , Triptofano/genética , Tunísia
16.
Am Heart J ; 225: 108-119, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32480058

RESUMO

INTRODUCTION: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. METHODS AND RESULTS: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10-5; U.S. cohort, P = 2.2×10-13). CONCLUSION: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.


Assuntos
Cardiomiopatias/genética , Heterozigoto , Mutação com Perda de Função , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Proteínas Quinases/genética , Anormalidades Múltiplas/genética , Adulto , Idade de Início , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Ecocardiografia , Eletrocardiografia , Humanos , Lactente , Fenótipo
17.
Einstein (Sao Paulo) ; 18: eRC5335, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32578677

RESUMO

Chromosomal abnormalities are responsible for several congenital malformations in the world, some of these are associated to telomeric/subtelomeric deletions. The abnormalities involving the telomere of chromosome 12 are rare, with few reports of deletions involving 12q24.31 region in the literature, and, to our knowledge, only four of them in the 12q24.31-q24.33 region. We report a further case of interstitial deletion of bands 12q24.31-q24.33 associated with autism spectrum disorder. A 2-year-old boy with global developmental delay associated with multiple congenital anomalies. The Human Genome CGH Microarray 60K confirmed the diagnosis of 12q deletion syndrome. This study made a review of the current literature comparing our patient with previously reported cases. These detailed analyses contribute to the development of genotype/phenotype correlations for 12q deletions that will aid in better diagnosis and prognosis of this deletion.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 12/genética , Doenças Raras/genética , Anormalidades Múltiplas , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Humanos , Masculino
19.
Cytogenet Genome Res ; 160(6): 309-315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32599602

RESUMO

Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by microcephaly, cortical dysplasia, intellectual disability, ocular abnormalities, spastic diplegia, and microgenitalia. WARBM has 4 subtypes arising from pathogenic variants in 4 genes (RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20). Here, we report on a patient with a homozygous pathogenic c.665delC (p.Pro222HisfsTer30) variant in the RAB3GAP1 gene identified by whole-exome sequencing (WES) analyses. Only his father was a heterozygous carrier, and homozygosity mapping analysis of the WES data revealed large loss-of-heterozygosity regions in both arms of chromosome 2, interpreted as uniparental isodisomy. This uniparental disomy pattern could be due to paternal meiosis I nondisjunction because of the preserved heterozygosity in the pericentromeric region. This report provides novel insights, including a rare form of UPD, usage of homozygosity mapping analysis for the evaluation of isodisomy, and the first reported case of WARBM1 as a result of uniparental isodisomy.


Assuntos
Anormalidades Múltiplas/genética , Catarata/congênito , Cromossomos Humanos Par 2/genética , Córnea/anormalidades , Homozigoto , Hipogonadismo/genética , Deficiência Intelectual/genética , Microcefalia/genética , Atrofia Óptica/genética , Dissomia Uniparental/genética , Sequenciamento Completo do Exoma , Adolescente , Adulto , Catarata/genética , Feminino , Humanos , Lactente , Perda de Heterozigosidade/genética , Masculino , Pais , Polimorfismo de Nucleotídeo Único/genética , Proteínas rab3 de Ligação ao GTP/genética
20.
J Card Surg ; 35(7): 1743-1745, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32485051

RESUMO

The association of absent right superior vena cava and persistent left superior vena cava draining into unroofed coronary sinus with common atrium and the atrioventricular septal defect is an extremely rare form of the congenital cardiac disorder with only one case reported so far, hence, can be missed preoperatively if not carefully looked for. Failure to detect absent right superior vena cava beforehand may otherwise pose difficulties in carrying out invasive surgical or medical interventions.


Assuntos
Anormalidades Múltiplas/cirurgia , Procedimentos Cirúrgicos Cardiovasculares/métodos , Seio Coronário/anormalidades , Seio Coronário/cirurgia , Defeitos dos Septos Cardíacos/cirurgia , Malformações Vasculares/cirurgia , Veia Cava Superior/anormalidades , Veia Cava Superior/cirurgia , Pré-Escolar , Ecocardiografia , Ecocardiografia Transesofagiana , Feminino , Átrios do Coração/anormalidades , Átrios do Coração/cirurgia , Defeitos dos Septos Cardíacos/diagnóstico por imagem , Humanos , Resultado do Tratamento
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