Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.072
Filtrar
1.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
2.
BMC Med Genet ; 21(1): 185, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32962661

RESUMO

BACKGROUND: Genetic eye diseases constitute a large and heterogeneous group of childhood ocular morbidity. Individual diseases may cause multiple structural anomalies and developmental features. Nepal Pediatric Ocular Disease Study (NPODS) was a population-based epidemiological study conducted across three ecological regions of Nepal to determine the prevalence and etiology of childhood ocular morbidity and blindness. In Phase II of this study, genetic analysis was performed for children who were found to have congenital ocular anomalies. METHOD: It was a cross sectional descriptive study. A total of 10,270 children across three different ecological regions in Nepal (Low lands, hills, and mountains) underwent ocular examinations in NPODS. Out of 374 (3.6%) of children with ocular abnormalities, 30 were thought to be congenital in nature. Targeted genetic analysis, including genotyping for genes specific to presenting phenotype, was performed for 25 children using serum samples. RESULTS: Out of 25 children, 18 had meaningful genetic results. Analysis revealed one missense alteration G12411T of Zinc Finger Homeobox 4 (ZFHX4) gene in one participant among 10 with congenital ptosis and another missense variation T > C P. Y374 C of Signaling Receptor and Transporter Retinol 6 (STRA6) gene in one participant among 3 with microphthalmos. CONCLUSION: The study is first of its kind from Nepal and mutant genes were unique to Nepalese Population. Further analysis of genetic factors is crucial to better understand genetic association with ocular diseases and conditions. This helps further in genetic counseling and probably gene therapy to prevent blindness from these conditions.


Assuntos
Cegueira/genética , Anormalidades Congênitas/genética , Oftalmopatias/genética , Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto , Adolescente , Altitude , Cegueira/diagnóstico , Cegueira/epidemiologia , Criança , Pré-Escolar , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/epidemiologia , Estudos Transversais , Oftalmopatias/diagnóstico , Oftalmopatias/epidemiologia , Feminino , Proteínas de Homeodomínio/genética , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/genética , Nepal/epidemiologia , Prevalência , Fatores de Transcrição/genética
3.
Mutat Res ; 785: 108320, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32800274

RESUMO

It is well established that maternal age is associated with a rapid decline in the production of healthy and high-quality oocytes resulting in reduced fertility in women older than 35 years of age. In particular, chromosome segregation errors during meiotic divisions are increasingly common and lead to the production of oocytes with an incorrect number of chromosomes, a condition known as aneuploidy. When an aneuploid oocyte is fertilized by a sperm it gives rise to an aneuploid embryo that, except in rare situations, will result in a spontaneous abortion. As females advance in age, they are at higher risk of infertility, miscarriage, or having a pregnancy affected by congenital birth defects such as Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Turner syndrome (monosomy X). Here, we review the potential molecular mechanisms associated with increased chromosome segregation errors during meiosis as a function of maternal age. Our review shows that multiple exogenous and endogenous factors contribute to the age-related increase in oocyte aneuploidy. Specifically, the weight of evidence indicates that recombination failure, cohesin deterioration, spindle assembly checkpoint (SAC) disregulation, abnormalities in post-translational modification of histones and tubulin, and mitochondrial dysfunction are the leading causes of oocyte aneuploidy associated with maternal aging. There is also growing evidence that dietary and other bioactive interventions may mitigate the effect of maternal aging on oocyte quality and oocyte aneuploidy, thereby improving fertility outcomes. Maternal age is a major concern for aneuploidy and genetic disorders in the offspring in the context of an increasing proportion of mothers having children at increasingly older ages. A better understanding of the mechanisms associated with maternal aging leading to aneuploidy and of intervention strategies that may mitigate these detrimental effects and reduce its occurrence are essential for preventing abnormal reproductive outcomes in the human population.


Assuntos
Aneuploidia , Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Segregação de Cromossomos/genética , Anormalidades Congênitas/genética , Idade Materna , Anormalidades Congênitas/prevenção & controle , Feminino , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/genética , Meiose/genética , Mitocôndrias/fisiologia , Oócitos/fisiologia
4.
Rev. bioét. derecho ; (49): 141-154, jul. 2020.
Artigo em Português | IBECS | ID: ibc-192099

RESUMO

O diagnóstico seguro de malformações congênitas possibilitado pelo avanço tecnológico da propedêutica fetal possibilita o exercício da autonomia reprodutiva da gestante, embora suscite dilemas éticos e jurídicos de difícil solução, como a opção pelo aborto e a tomada de decisões em neonatos com escassas possibilidades de sobrevivência. As decisões em fim de vida e o abandono de técnicas terapêuticas fúteis que não alteram o curso natural da doença despertam conflitos éticos entre a equipe de saúde e os familiares. Nesse cenário, importa analisar o âmbito de proteção aos direitos das pessoas com deficiência no Brasil e sua aplicação aos neonatos com graves malformações congênitas, visando contribuir ao debate sobre a morte digna no período neonatal


El diagnóstico efectivo de malformaciones congénitas que resulta del avance tecnológico de la propedéutica fetal posibilita el ejercicio de la autonomía reproductiva de la mujer embarazada, aunque presente dilemas éticos y jurídicos de solución difícil, como la opción por el aborto y la toma de decisiones en casos de recién nacidos con baja posibilidad de sobrevivir. Decisiones de fin de la vida y el abandono de técnicas terapéuticas fútiles que no cambian la evolución natural de la enfermedad producen conflictos éticos entre el equipo de salud y la familia. En ese escenario, es importante analizar el ámbito de protección a los derechos de las personas con deficiencia en Brasil y su aplicación a los recién nacidos con malformaciones congénitas graves, con el objetivo de contribuir al debate sobre la muerte digna en el periodo neonatal


The diagnostic certainty of congenital malformations, made possible by the technological advances in fetal propaedeutics, enables the exercise of reproductive autonomy by the pregnant woman, although it results in ethical and legal dilemmas that are difficult to solve, such as the option for abortion, and decision-making regarding newborns with meager survival possibility. End-of-life decisions and the abandonment of futile therapeutic techniques that do not alter the natural course of the illness give rise to ethical conflicts between the health team and family members. In this setting, it is important to analyze the scope of protection of the rights of handicapped persons in Brazil, and how it applies to the newborn with severe congenital malformations, with the goal of contributing to dignified death in the neonatal period


El diagnòstic efectiu de malformacions congènites que resulta de l'avanç tecnològic de la propedèutica fetal possibilita l'exercici de l'autonomia reproductiva de la dona embarassada, encara que presenta dilemes ètics I jurídics de solució difícil, com l'opció per l'avortament I la presa de decisions en casos de nounats amb baixa possibilitat de sobreviure. Les decisions de final de la vida I l'abandonament de tècniques terapèutiques fútils que no canvien l'evolució natural de la malaltia donen lloc a conflictes ètics entre l'equip de salut I la família. En aquest escenari, és important analitzar l'àmbit de protecció dels drets de les persones amb deficiència a Brasil I la seva aplicació als nadons amb malformacions congènites greus, a fi de contribuir al debat sobre la mort digna en el període neonatal


Assuntos
Humanos , Gravidez , Recém-Nascido , Anormalidades Congênitas/genética , Temas Bioéticos , Tomada de Decisões/ética , Doenças do Recém-Nascido/genética , Futilidade Médica/ética , Viabilidade Fetal/genética , Brasil , Futilidade Médica/legislação & jurisprudência , Defesa da Criança e do Adolescente/ética , Diagnóstico Pré-Natal/ética , Troca Materno-Fetal/genética
5.
Adv Clin Exp Med ; 29(4): 505-511, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32348039

RESUMO

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also known as Müllerian agenesis or aplasia, is a congenital disease manifested by the aplasia of the uterus and the upper 2/3 of the vagina; its incidence is 1 in 4,000-5,000 female live births. We can distinguish 2 types of the MRKH syndrome: type I, which is characterized by an isolated absence of 2/3 of the vagina and uterus; and type II or MURCS (Müllerian duct aplasia, unilateral renal agenesis and cervicothoracic somite anomalies), which is also associated with other symptoms. The treatment of the MRKH syndrome patients aims at creating a neovagina and enabling sexual intercourse. Non-surgical techniques are the first-choice methods, and more than 90% of patients notice an anatomical and functional improvement if they are well-prepared emotionally. If non-surgical treatment does not bring about the expected results, a surgical procedure remains an option. The surgical method is mainly determined by the surgeon's experience. There are a few types of operations, though none of them seems superior to others. The next challenge is to provide these patients with a chance to become parents. Nowadays, a uterine transplant, a surrogate or adoption are the available solutions. An interdisciplinary approach is required, and the treatment should consist of medical and psychological support. This review presents the current knowledge about the MRKH syndrome with regard to the current methods of non-surgical and surgical treatment as well as a summary of the associated psychological problems.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual , Anormalidades Congênitas , Ductos Paramesonéfricos/anormalidades , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Transtornos 46, XX do Desenvolvimento Sexual/genética , Transtornos 46, XX do Desenvolvimento Sexual/cirurgia , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Anormalidades Congênitas/cirurgia , Feminino , Humanos , Ductos Paramesonéfricos/cirurgia , Útero/anormalidades , Vagina/anormalidades
6.
Nat Rev Cancer ; 20(7): 383-397, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32341551

RESUMO

Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death. Although oncoproteins were discovered many years ago and have been widely studied in the context of cancer, the recent use of high-throughput sequencing techniques has led to the identification of cancer-associated mutations in other conditions, including many congenital disorders. These syndromes offer an opportunity to study oncoprotein signalling and its biology in the absence of additional driver or passenger mutations, as a result of their monogenic nature. Moreover, their expression in multiple tissue lineages provides insight into the biology of the proto-oncoprotein at the physiological level, in both transformed and unaffected tissues. Given the recent paradigm shift in regard to how oncoproteins promote transformation, we review the fundamentals of genetics, signalling and pathogenesis underlying oncoprotein duality.


Assuntos
Transformação Celular Neoplásica/metabolismo , Anormalidades Congênitas/genética , Doenças Genéticas Inatas/genética , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Transformação Celular Neoplásica/genética , Anormalidades Congênitas/metabolismo , Modelos Animais de Doenças , Interação Gene-Ambiente , Doenças Genéticas Inatas/metabolismo , Humanos , Camundongos , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Transdução de Sinais
7.
Acta Obstet Gynecol Scand ; 99(6): 783-790, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32304219

RESUMO

INTRODUCTION: Applying whole-exome sequencing (WES) for the diagnosis of diseases in children has shown significant diagnostic strength compared with chromosomal microarray. WES may also have the potential of adding clinically relevant prenatal information in cases where a fetus is found to have structural anomalies. We present results from the first fetal exomes performed in a tertiary center in Denmark. MATERIAL AND METHODS: Couples/expectant parents were included in Central Denmark Region from July 2016 to March 2019. Inclusion was not systematic, but where one or more fetal malformations or severe fetal hydrops were detected, and a specific diagnosis had not been obtained by chromosomal microarray. WES was performed in ongoing pregnancies (N = 11), after intrauterine demise (N = 5), or after termination of pregnancy based on ultrasound findings (N = 19). In most cases, a trio format was applied comprising fetal and parental DNA. RESULTS: WES was performed in 35 highly selected fetal cases. Pathogenic variants, or variants likely to explain the phenotype, were detected in 9/35 (26%). Variants of uncertain significance were detected in 7/35 (20%) and there was one secondary finding (3%). Out of the 11 ongoing pregnancies, four reached a genetic diagnosis (36%). Detection rate was highest in cases of multisystem anomalies (7/13, 54%). WES was completed in all three trimesters and both autosomal dominant, autosomal recessive and X-linked inheritance were revealed. CONCLUSIONS: We present data from 35 cases of exome sequencing applied in a setting of fetal malformations. Importantly, though, we wish to share our personal experiences with implementing WES into a prenatal setting. As a medical society, we must continue to share what we do not understand, what went wrong, what is difficult, and what we do not agree upon. A common understanding and language are warranted. We also advocate that more research is needed concerning the clinical value, as well as costs and patient perspectives, of using WES in pregnancy. We believe that WES will lead to improved prenatal and perinatal care.


Assuntos
Anormalidades Congênitas/genética , Feto/anormalidades , Sequenciamento Completo do Exoma , Anormalidades Congênitas/diagnóstico por imagem , Dinamarca , Feminino , Desenvolvimento Fetal/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Gravidez , Diagnóstico Pré-Natal , Estudos Retrospectivos , Ultrassonografia Pré-Natal
8.
Proc Natl Acad Sci U S A ; 117(7): 3738-3747, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32015132

RESUMO

Causes for miscarriages and congenital malformations can be genetic, environmental, or a combination of both. Genetic variants, hypoxia, malnutrition, or other factors individually may not affect embryo development, however, they may do so collectively. Biallelic loss-of-function variants in HAAO or KYNU, two genes of the nicotinamide adenine dinucleotide (NAD) synthesis pathway, are causative of congenital malformation and miscarriage in humans and mice. The variants affect normal embryonic development by disrupting the synthesis of NAD, a key factor in multiple biological processes, from its dietary precursor tryptophan, resulting in NAD deficiency. This study demonstrates that congenital malformations caused by NAD deficiency can occur independent of genetic disruption of NAD biosynthesis. C57BL/6J wild-type mice had offspring exhibiting similar malformations when their supply of the NAD precursors tryptophan and vitamin B3 in the diet was restricted during pregnancy. When the dietary undersupply was combined with a maternal heterozygous variant in Haao, which alone does not cause NAD deficiency or malformations, the incidence of embryo loss and malformations was significantly higher, suggesting a gene-environment interaction. Maternal and embryonic NAD levels were deficient. Mild hypoxia as an additional factor exacerbated the embryo outcome. Our data show that NAD deficiency as a cause of embryo loss and congenital malformation is not restricted to the rare cases of biallelic mutations in NAD synthesis pathway genes. Instead, monoallelic genetic variants and environmental factors can result in similar outcomes. The results expand our understanding of the causes of congenital malformations and the importance of sufficient NAD precursor consumption during pregnancy.


Assuntos
Aborto Espontâneo/genética , Anormalidades Congênitas/genética , Interação Gene-Ambiente , NAD/deficiência , Aborto Espontâneo/metabolismo , Animais , Anormalidades Congênitas/metabolismo , Embrião de Mamíferos/metabolismo , Feminino , Humanos , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
9.
Gene ; 731: 144360, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31935506

RESUMO

Kabuki syndrome (KS) is a rare congenital disorder characterized by distinctive facies, postnatal growth deficiency, cardiac defects and skeletal anomalies. Studies have determined that pathogenic variants of the lysine-specific methyltransferase 2D (KMT2D) and lysine-specific demethylase 6A (KDM6A) genes are the major causes of KS. The two genes encode different histone-modifying enzymes that are found in the same protein complex that is critical for cell differentiation during development. Here we report the results from next-generation sequencing of genomic DNA from 13 patients who had a clinical diagnosis of KS based on facial dysmorphism and other KS-specific cardinal phenotypes. Nine of the 13 patients were confirmed to be carrying heterozygous pathogenic KMT2D variants, seven of which were truncating and two were missense substitutions. Overall, we uncovered 11 novel variants - nine in KMT2D and two in KDM6A. Seven of the novel variants (all KMT2D) were likely causative of the KS phenotype. Our study expands the number of naturally occurring KMT2D and KDM6A variants. The discovery of novel pathogenic variants will add to the knowledge on disease-causing variants and the relevance of missense variants in KS.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Congênitas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/genética , Histona Desmetilases/genética , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/epidemiologia , Ásia Sudeste/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Anormalidades Congênitas/epidemiologia , Análise Mutacional de DNA/métodos , Feminino , Doenças Hematológicas/epidemiologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Fenótipo , Análise de Sequência de DNA , Doenças Vestibulares/epidemiologia
10.
Rev Paul Pediatr ; 38: e2018318, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31939516

RESUMO

OBJECTIVE: For every 100 random children diagnosed with autism, at least 20 have morphological abnormalities, often associated with syndromes. Brazil does not have a standardized and validated instrument for morphological physical examination. This study aimed to translate into Brazilian Portuguese and culturally adapt the clinical signs described in the Autism Dysmorphology Measure, as well as validate the instrument in a sample of children with autism. METHODS: The original instrument was translated, culturally adapted, and published in full, following traditional procedures for translation, back-translation, and terminology adaptation according to the Nomina Anatomica. The sample included 62 children from a published multicenter study, with intelligence quotient between 50-69, of both genders, with chronological age between 3-6 years. Two clinical geneticists performed the morphological physical examination, which consisted of investigating 82 characteristics assessing 12 body areas. We used Cohen's Kappa coefficient to evaluate the agreement between the two observers. RESULTS: The final version of the instrument - translated into Brazilian Portuguese and culturally adapted - showed high agreement between the two observers. CONCLUSIONS: The translated instrument meets all international criteria, and minor anomalies and their clinical descriptions were standardized and are recognizable for physicians not specialized in genetics.


Assuntos
Adaptação Psicológica/fisiologia , Transtorno do Espectro Autista/psicologia , Anormalidades Congênitas/diagnóstico , Exame Físico/métodos , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Transtornos Dismórficos Corporais/psicologia , Brasil/epidemiologia , Criança , Pré-Escolar , Anormalidades Congênitas/genética , Características Culturais , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Inquéritos e Questionários , Traduções
11.
Congenit Anom (Kyoto) ; 60(1): 4-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30629771

RESUMO

The aim of this study is to evaluate the significance of renal pelvis aspiration (RPA) in the management of antenatal hydronephrosis (AHN). This study enrolled 15 AHN cases (one twin pregnancy) that necessitated RPA for AHN. Chromosomal abnormalities, gene disorders, and additional life-threatening congenital abnormalities were eliminated prior to intrauterine interventions. Urine analysis were performed for the evaluation of renal function. Normal renal function was observed in six neonates/infants (40%) (group 1), whereas impaired renal function and various type of urinary system anomalies were observed in 9 neonates/infants (60%) (group 2) during the short-term and longitudinal follow-up periods. There were statistically significant differences in the oligohydroamniosis rate, mean fetal urine sodium value, mean fetal urine ß2-microglobulin, mean gestational week at birth, and mean birthweight values between the groups (P = 0.007, P < 0.001, P = 0.035, P < 0.001, and P = 0.001, respectively). Renal pelvis aspiration and urine analysis were substantial for the management of AHN in necessary cases. ß2-microglobulin and sodium are clinically useful markers to detect the presence of severe renal damage due to obstructive uropathy and thus, important adjuvants in the proper selection of fetuses for further antenatal interventions.


Assuntos
Anormalidades Congênitas/genética , Doenças Fetais/urina , Hidronefrose/urina , Diagnóstico Pré-Natal , Anormalidades Congênitas/patologia , Anormalidades Congênitas/urina , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/patologia , Idade Gestacional , Humanos , Hidronefrose/diagnóstico por imagem , Hidronefrose/patologia , Recém-Nascido , Rim/metabolismo , Rim/patologia , Pelve Renal/diagnóstico por imagem , Pelve Renal/patologia , Masculino , Gravidez , Fatores de Risco , Ultrassonografia Pré-Natal/métodos , Anormalidades Urogenitais/diagnóstico por imagem , Anormalidades Urogenitais/patologia , Anormalidades Urogenitais/urina , Microglobulina beta-2/urina
12.
J Clin Lab Anal ; 34(1): e23025, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31506986

RESUMO

BACKGROUND: While congenital anomalies of the kidney and urinary tract (CAKUT) constitute one-third of all congenital malformations, the mechanisms underlying their development are poorly understood. Some studies have reported an association between CAKUT and copy number variations (CNVs) in children and adults, but few have focused on chromosomal microarray analysis (CMA) findings in fetuses with CAKUT. Therefore, we aimed to perform a CMA on fetuses with CAKUT and normal karyotypes in the presence and absence of other structural anomalies. METHOD: The study was conducted in 147 fetuses with CAKUT and normal karyotypes between January 2016 and January 2019 in the Fujian Provincial Maternal and Child Health Hospital. Single nucleotide polymorphism (SNP) analysis was performed using the Affymetrix CytoScan HD platform. RESULTS: The SNP array identified abnormal CNVs in 13 cases (8.8%): Six were pathogenic, and seven were variations of uncertain clinical significance (VOUS). The detection rate of abnormal CNVs in non-isolated CAKUT was higher than that in isolated CAKUT (22.7% vs 6.4%, P = .038). Within the abnormal CNV groups, the highest frequency of CNVs was identified in fetuses with polycystic kidney dysplasia (13.5%), followed by those with renal agenesis (10.5%). CONCLUSION: SNP array is effective for identifying chromosomal abnormalities in CNVs in fetuses with CAKUT and normal karyotypes, and help counseling.


Assuntos
Anormalidades Congênitas/genética , Variações do Número de Cópias de DNA/genética , Feto/anormalidades , Rim/anormalidades , Análise em Microsséries , Polimorfismo de Nucleotídeo Único/genética , Sistema Urinário/anormalidades , Humanos , Cariotipagem
13.
Oncogene ; 39(3): 516-529, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541194

RESUMO

Cells are repeatedly exposed to environmental or endogenous stresses that can alter normal cell behavior and increase cell vulnerability. In order to ensure tissue integrity and function, cells cope with cellular injuries by adapting their metabolism, protecting essential intracellular constituents, inhibiting cell death signaling pathways and activating those devoted to damage repair. The molecular chaperones of the heat-shock protein (HSP) family are critical effectors of this adaptive response. They protect intracellular proteins from misfolding or aggregation, inhibit cell death signaling cascades and preserve the intracellular signaling pathways that are essential for cell survival. Most HSPs are rapidly overexpressed in response to cellular injuries including genotoxic stress. DNA damage can dramatically alter cell behavior and contribute to a number of diseases including developmental defects, neurodegenerative disorders, and cancer. Thus, the ability of cells to repair DNA damage is essential for preserving cell integrity. DNA damage activates a coordinated response that includes detecting DNA lesions before their transmission to daughter cells, blocking cell cycle progression and DNA replication and repairing the damage. Although the role of HSPs in proteins homeostasis and cell death, especially apoptosis has been widely reported, much less is known about their function in DNA repair. This review aims to present the role of HSPs in DNA repair signaling pathways.


Assuntos
Anormalidades Congênitas/genética , Reparo do DNA , Proteínas de Choque Térmico/metabolismo , Neoplasias/genética , Doenças Neurodegenerativas/genética , Animais , Apoptose/genética , Sobrevivência Celular , Anormalidades Congênitas/patologia , Dano ao DNA , Instabilidade Genômica , Humanos , Neoplasias/patologia , Doenças Neurodegenerativas/patologia , Dobramento de Proteína , Transdução de Sinais/genética
14.
Congenit Anom (Kyoto) ; 60(1): 22-31, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30785647

RESUMO

In a previous article we reported that mutations favoring cancer at adulthood seemed to improve fertility and limit miscarriages. Because spontaneous abortion may result from anomalies in embryo, we questioned if an increased frequency of congenital malformation could be evidenced among cancer-prone families. Oncogenetics database (≈193 000 members) of the comprehensive cancer center Jean Perrin was crossed with regional registry of congenital malformations (≈10 000). Among children born between 1986 and 2011, 176 children with malformation matched in both databases. In breast/ovaries cancer-prone families, the risk for malformations was multiplied by 2.4 [1.2-4.5] in case of a BRCA1 mutation. Frequencies of malformation in BRCA2 and MMR mutated families were similar to families without a cancer syndrome. In comparison to malformations concerning a unique anatomical system, multimalformations were significantly more frequent in case of BRCA or MMR mutations: compared to families without cancer syndrome, the risk of multimalformations was multiplied by 4.1 [0.8-21.7] for cancer-prone families but with no known deleterious mutation, by 6.9 [1.2-38.6] in families with a known mutation but an unknown parental mutational status and by 10.4 [2.3-46.0] when one parent carried the familial mutation. No association with the type of anatomical system was found, nor with multiple births. These results suggest that BRCA and MMR genes play an important role in human embryogenesis and that if their function is lowered because of heterozygote mutations, congenital malformations are either more likely (BRCA1 mutations) and/or more susceptible to concern several anatomical systems.


Assuntos
Neoplasias da Mama/genética , Anormalidades Congênitas/genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Aborto Espontâneo/genética , Aborto Espontâneo/patologia , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Criança , Anormalidades Congênitas/patologia , Desenvolvimento Embrionário/genética , Feminino , Estudos de Associação Genética , Mutação em Linhagem Germinativa/genética , Humanos , Neoplasias Ovarianas/patologia , Linhagem , Receptores Imunológicos/genética
15.
J Hum Genet ; 65(3): 221-230, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31827250

RESUMO

Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher's exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-ß) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS.


Assuntos
Anormalidades Congênitas/genética , Fibrilina-1/genética , Predisposição Genética para Doença , Escoliose/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/fisiopatologia , Exoma/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação , Mutação de Sentido Incorreto/genética , Linhagem , Escoliose/diagnóstico por imagem , Escoliose/fisiopatologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/fisiopatologia , Fator de Crescimento Transformador beta/genética
16.
J Dermatol ; 47(1): 78-81, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31692010

RESUMO

Port-wine stains (PWS) are capillary malformations associated with mutation in the GNAQ (NM_000441.1) gene. Large vestibular aqueduct syndrome (LVAS), caused by mutation in the SLC26A4 (NM_002072) gene, is an inner ear malformation that can lead to hearing loss. To our knowledge, LVAS in PWS patients has never been reported. Here, we describe a case of a 9-year-old female patient diagnosed with PWS on the face and neck, coexisting with large vestibular aqueduct syndrome. Further analyses revealed a somatic mutation in GNAQ and a compound heterozygous mutation in the SLC26A4 gene. Some PWS patients have associated abnormalities, such as glaucoma and choroidal hemangioma, leptomeningeal angiomas and atrophy or hypertrophy of bone and soft tissue. We present here the first case that reveals the possibility that capillary malformations are associated with inner ear malformation. More case reports and further studies are needed to determine whether these conditions coexist in other patients.


Assuntos
Anormalidades Congênitas/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Perda Auditiva Neurossensorial/genética , Mancha Vinho do Porto/genética , Transportadores de Sulfato/genética , Aqueduto Vestibular/anormalidades , Criança , Feminino , Perda Auditiva Neurossensorial/complicações , Humanos , Mutação , Síndrome
17.
Artigo em Inglês | MEDLINE | ID: mdl-31836586

RESUMO

A 4-yr-old female with congenital knee dislocations and joint laxity was noted to have a strong maternal family history comprising multiple individuals with knee problems and clubfeet. As the knee issues were the predominant clinical features, clinical testing included sequencing of LMX1B, TBX2, and TBX4, which identified no significant variants. Research genome sequencing was performed in the proband, parents, and maternal grandfather. A heterozygous in-frame deletion in FLNB c. 5468_5470delAGG, which predicts p.(Glu1823del), segregated with the disease. The variant is rare in the gnomAD database, removes a residue that is evolutionarily conserved, and is predicted to alter protein length. Larsen syndrome may present with pathology that primarily involves one joint and thus may be difficult to differentiate clinically from other skeletal dysplasias or arthrogryposis syndromes. The p.(Glu1823del) variant maps to a filamin repeat domain where other disease-causing variants are clustered, consistent with a probable gain-of-function mechanism. It has reportedly been observed in two individuals in the gnomAD database, suggesting that mild presentations of Larsen syndrome, like the individual reported here, may be underdiagnosed in the general population.


Assuntos
Filaminas/genética , Luxação do Joelho/genética , Osteocondrodisplasias/genética , Anormalidades Múltiplas/genética , Adulto , Sequência de Bases/genética , Pré-Escolar , Anormalidades Congênitas/genética , Família , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Deleção de Sequência/genética
18.
Ceska Gynekol ; 84(5): 386-392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31826637

RESUMO

OBJECTIVE: Evaluation of existing knowledge of etiopathogenesis, clinical manifestations and treatment options to increase quality of life in women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH). DESIGN: Review article. SETTING: Department of Obstetrics and Gynaecology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague. METHODS: Literature search using the Web of Science, Google Scholar and Medline databases with keywords (absolute uterine infertility factor, AUFI, Mayer-Rokitansky-Küster-Hauser syndrome, MRKH, uterine transplantation) and analysis of articles published in impact and reviewed journals. RESULTS: MRKH syndrome is defined as congenital agenesis of the upper two-thirds of vagina and uterus in women with normal secondary sexual characteristics and female karyotype (46, XX). The incidence of the syndrome is 1 : 4500 births of female sex children. It is the second most common cause of primary amenorrhea. Recent research has focused on elucidating the genetic origin of the disease, focusing on the research of candidate genes that could be participating in the genesis of Müllerian ducts and their derivatives. CONCLUSION: MRKH syndrome now appears as a multifactorial congenital developmental defect based on a combination of genetic predisposition and environmental factors. Modern medicine can help girls with MRKH syndrome to a quality sexual life. It is also able to offer different possibilities of achieving motherhood. In the future, however, further research is needed, in particular on the etiology and pathogenesis of this syndrome to detect a possible genetic basis of the disease.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual , Anormalidades Congênitas/genética , Vagina/anormalidades , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Transtornos 46, XX do Desenvolvimento Sexual/genética , Criança , Feminino , Humanos , Qualidade de Vida , Útero
20.
Curr Opin Pediatr ; 31(6): 702-707, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31693576

RESUMO

PURPOSE OF REVIEW: Dysmorphic features result from errors in morphogenesis frequently associated with genetic syndromes. Recognizing patterns of dysmorphic features is a critical step in the diagnosis and management of human congenital anomalies and genetic syndromes. This review presents recent developments in genetic syndromes and their related dysmorphology in diverse populations. RECENT FINDINGS: Clinical findings in patients with genetic syndromes differ in their heterogeneity across different population groups. Some genetic syndromes have variable features in different ethnicities, in part due to specific background exam characteristics such as flat facial profiles or nasal differences; however, other genetic syndromes are similar across different ethnicities. Facial analysis technology is accurate in diagnosing genetic syndromes in populations around the world and is a powerful adjunct to conventional clinical examination. This accuracy also reinforces the concept that genetic syndromes can and should be diagnosed in any ethnicity. SUMMARY: The increasing amount of data from studies on genetic syndromes in diverse populations is significantly improving our knowledge and approach to dysmorphic patients from various ethnic backgrounds. Optimal management of genetic syndromes requires early diagnosis, including in developing countries.


Assuntos
Anormalidades Congênitas/genética , Anormalidades Craniofaciais/genética , Face , Anormalidades Congênitas/diagnóstico , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA