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1.
Adv Exp Med Biol ; 1166: 29-46, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31301044

RESUMO

Spermatogenesis is a highly complex biological process during which germ cells undergo recurrent rounds of DNA replication and cell division that may predispose to random mutational events. Hence, germ cells are vulnerable to the introduction of a range of de novo mutations, in particular chromosomal aberrations, point mutations and small indels. The main mechanisms through which mutations may occur during spermatogenesis are (i) errors in DNA replication, (ii) inefficient repair of non-replicative DNA damage between cell divisions and (iii) exposure to mutagens during lifetime. Any genetic alteration in the spermatozoa, if not repaired/eliminated, can be passed on to the offspring, potentially leading to malformations, chromosomal anomalies and monogenic diseases. Spontaneous de novo mutations tend to arise and accumulate with a higher frequency during testicular aging. In fact, there is an increased incidence of some chromosomal aberrations and a greater risk of congenital disorders, collectively termed paternal age effect (PAE), in children conceived by fathers with advanced age. PAE disorders are related to well-characterized de novo point mutations leading to a selective advantage on the mutant spermatogonial stem cells that cause a progressive enrichment over time of mutant spermatozoa in the testis.The purpose of this chapter is to provide a summary on the spontaneous genetic alterations that occur during spermatogenesis, focusing on their underlying mechanisms and their consequences in the offspring.


Assuntos
Células-Tronco Germinativas Adultas , Anormalidades Congênitas , Mutação , Idade Paterna , Espermatogênese , Anormalidades Congênitas/etiologia , Anormalidades Congênitas/genética , Humanos , Masculino , Espermatogênese/genética , Espermatozoides , Testículo
2.
Hum Genet ; 138(10): 1105-1115, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31230195

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33-34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.


Assuntos
Colágeno Tipo IV/genética , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Rim/anormalidades , Mutação , Fenótipo , Sistema Urinário/anormalidades , Alelos , Substituição de Aminoácidos , Biologia Computacional/métodos , Análise Mutacional de DNA , Bases de Dados Genéticas , Evolução Molecular , Feminino , Estudos de Associação Genética , Loci Gênicos , Genômica/métodos , Heterozigoto , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Masculino , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Navegador , Sequenciamento Completo do Exoma
3.
Methods Mol Biol ; 1965: 421-434, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31069690

RESUMO

Teratology is the study of anatomical and physiological abnormalities, commonly known as birth defects. If an embryo is exposed to a harmful substance, or teratogen, during the critical period of development, an ensuing malformation may occur. These malformations and their associated mechanisms are studied and analyzed in laboratory animals in order to prevent them from occurring in humans. Rodents such as rats and mice have commonly been used in such studies because of their similarity to humans. In 1959, James G. Wilson designed, developed, and tested a protocol on how to observe and analyze structural malformations in rodent fetuses, which included: external examination, skeletal evaluation, soft tissue analysis, and data collection/analysis. For standardization purposes, i.e., to normalize findings from one lab to another, it is important that this protocol be followed with precision. Although many years have passed since Wilson initially created this protocol, it is still widely used to this day, and only minor changes have been made to his instructions such as the chemical reagents used in the experiments and methods of analysis of the experimental data. Such testing has resulted in major advances in the dissemination of teratology information, including the identification of an increasing number of teratogens and the understanding of the pathogenesis of birth defects. While mechanistically birth defect prevention will include the understanding of individual genomes and pharmacogenomics, overall, morphological assessment will still be required as an integral part of birth defects research. As the interaction between teratogenic and genetic factors is better understood, it is anticipated that the incidence of most types of defects will substantially be reduced.


Assuntos
Anormalidades Induzidas por Medicamentos/diagnóstico , Anormalidades Congênitas/diagnóstico , Teratogênios/toxicidade , Anormalidades Induzidas por Medicamentos/genética , Animais , Osso e Ossos/anormalidades , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/embriologia , Anormalidades Congênitas/genética , Feminino , Feto/anormalidades , Feto/efeitos dos fármacos , Humanos , Camundongos , Gravidez , Ratos
4.
Gene ; 704: 1-7, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30970275

RESUMO

Mitochondrial homoplasmy is essential for normal development, as its heteroplasmy usually leads to abnormal or diseased phenotypes in mammals. So far, diverse mechanisms have been proposed to play roles in ensuring uniparental inheritance of mitochondria in many organisms. In recent years, hybrid yellow catfish from mating female yellow catfish (Pelteobagrus fulvidraco) with male darkbarbel catfish (Pelteobagrus vachelli) has been widely cultured in China due to its fast-growing. However, a high rate of abnormal and defective embryos was observed in the offsprings of hybrid yellow catfish. In this study, we systematically investigated the elimination process of paternal mitochondrial DNA (mtDNA) in yellow catfish and hybrid yellow catfish. The mtDNA contents significantly decreased in the isolated mature sperm compared with the semen. Different from the elimination of paternal mtDNA after fertilization in yellow catfish, paternal mtDNA was retained in the developmental embryos of hybrid yellow catfish as later as gastrula stage, indicating a delay of elimination for paternal mtDNA and mitochondrial heteroplasmy during embryogenesis in hybrid yellow catfish. Altogether, the present study suggests that mitochondrial heteroplasmy may affect embryonic development of hybrid progeny between catfish species.


Assuntos
Peixes-Gato/genética , DNA Mitocondrial/metabolismo , Desenvolvimento Embrionário/genética , Hibridização Genética , Herança Paterna/genética , Animais , Peixes-Gato/classificação , Anormalidades Congênitas/genética , Anormalidades Congênitas/veterinária , Feminino , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Desnaturação de Ácido Nucleico
5.
Zhonghua Fu Chan Ke Za Zhi ; 54(4): 221-225, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31006186

RESUMO

Objective: To investigate pathogenic genes related to the phenotype of fetus with severely short limbs in the first and second trimester by whole exome sequencing (WES). Methods: Thirteen fetuses with severely short limbs detected by ultrasonography in the first and second trimester admitted in Chinese PLA General Hospital from September 2016 to June 2018 were collected. All cases were performed induced abortion, 6 of which were carried out karyotype analysis of amniotic fluid at the same time. WES and copy number variations (CNV) were performed on specimens from fetal tissues after labor induction. The suspected pathogenic mutations were validated by Sanger sequencing reactions. Results: No abnormal karyotypes or pathological CNV were found. In 10 fetuses, pathogenic or possibly pathogenic mutations were detected in the following genes: COL2A1, FGFR3, COL1A1, COL1A2, DYNC2LI1 and TRIP11, all of which were essential to skeletal development. The diagnostic yield of WES in the fetuses with severe short limbs was 10/13. Conclusions: In the first and second trimester, most of the fetuses with extremely short limbs suffer from monogenic diseases. WES is likely to be a valuable diagnostic testing option for the fetuses with severe short limbs.


Assuntos
Anormalidades Congênitas/genética , Dineínas do Citoplasma , Variações do Número de Cópias de DNA , Desenvolvimento Fetal/genética , Feto/anormalidades , Sequenciamento Completo do Exoma/métodos , Anormalidades Congênitas/diagnóstico , Variações do Número de Cópias de DNA/genética , Feminino , Feto/diagnóstico por imagem , Humanos , Cariotipagem , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Ultrassonografia Pré-Natal
6.
Cytogenet Genome Res ; 157(3): 141-147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947196

RESUMO

Chromosomal microarray (CMA) is currently considered as a first-tier test in the genetic assessment of patients presenting with intellectual disability and/or multiple congenital abnormalities. The distinction between pathogenic CNVs, polymorphisms, and variants of unknown significance can be a diagnostic dilemma for cytogeneticists. The size of the CNV has been proposed as a useful criterion. We herein report the characterization of a 13.6-Mb interstitial duplication 20p11.1p12.1, found in a child presenting with mild global developmental delay, by standard karyotype and CMA. Unexpectedly, the same CNV was detected in the patient's mother and pregnant sister, who were healthy. On the basis of these results, an implication of this CNV in the neurological problems observed in the proband was considered to be unlikely. This report underlines the complexity of genetic counseling concerning rare chromosomal abnormalities, when little information is available either in the literature or in international cytogenetic databases.


Assuntos
Duplicação Cromossômica , Coloração Cromossômica/métodos , Anormalidades Congênitas/genética , Deficiência Intelectual/genética , Criança , Variações do Número de Cópias de DNA , Feminino , Aconselhamento Genético , Humanos , Masculino , Mães , Linhagem , Irmãos
7.
Eur J Endocrinol ; 180(6): 397-406, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30991358

RESUMO

Objective Turner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup. Design and methods This national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87). Results Median age was 9.4 (3.7-13.7) years at first evaluation and 16.8 (11.2-21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P < 0.0001). The cumulative incidence of subsequent acquired conditions, such as thyroid disease, hearing loss, overweight/obesity, dyslipidemia and, to a lesser extent, celiac disease, glucose intolerance/type 2 diabetes, hypertension and liver dysfunction increased with age, but less markedly for patients with mosaicism than for those with other karyotypes. Patients with a ring chromosome were more prone to metabolic disorders. Conclusion These data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.


Assuntos
Cromossomos Humanos X/genética , Anormalidades Congênitas/genética , Dosagem de Genes , Síndrome de Turner/genética , Adolescente , Adulto , Fatores Etários , Criança , Estudos de Coortes , Comorbidade , Anormalidades Congênitas/epidemiologia , Feminino , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Cariótipo , Rim/anormalidades , Nefropatias/congênito , Nefropatias/epidemiologia , Nefropatias/genética , Mosaicismo , Estudos Retrospectivos , Fatores de Risco , Síndrome de Turner/classificação , Síndrome de Turner/complicações , Adulto Jovem
8.
Arch Dis Child Fetal Neonatal Ed ; 104(4): F452-F456, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30816854

RESUMO

Major congenital anomalies are often associated with perinatal mortality, long-term morbidity and prolonged hospitalisation. Prenatal ultrasound remains the principle diagnostic test for many anomalies, but despite this up to one-third are only identified in the neonatal period. The primary step in determining underlying aetiology is to define accurately the phenotype by recognition of dysmorphology (both prenatally and postnatally). The potential introduction of next-generation sequencing, primarily through exome sequencing, into perinatal practice may improve the pathological diagnostic yield. However, clinicians must understand both the benefit and potential harms of this technology in facilitating the discovery of relevant pathogenic variants in the diagnosis and management of congenital malformations.


Assuntos
Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Diagnóstico Pré-Natal/métodos , Sequenciamento Completo do Exoma/estatística & dados numéricos , Feminino , Humanos , Recém-Nascido , Gravidez , Análise de Sequência de DNA/métodos
9.
Eur J Endocrinol ; 180(5): 291-309, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30893644

RESUMO

Context Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B″gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. Patients and methods Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics. Results We have identified three different homozygous PPP2R3C variants, c.308T>C (p.L103P), c.578T>C (p.L193S) and c.1049T>C (p.F350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility. Conclusion Our findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.


Assuntos
Disgenesia Gonadal 46 XY/genética , Proteína Fosfatase 2/genética , Espermatogênese/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Anormalidades Congênitas/genética , Consanguinidade , Feminino , Disgenesia Gonadal 46 XY/patologia , Homozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Mutação , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição SOX9/genética , Síndrome , Testículo/embriologia , Testículo/patologia
10.
Front Biosci (Landmark Ed) ; 24: 870-889, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844719

RESUMO

Congenital and genetic disorders cause many diseases in Arab countries due to large family sizes and high levels of inbreeding. Saudi Arabia (SA) has the highest consanguinity rates among Middle Eastern countries (~60% of all marriages) and is burdened by the highest number of genetic diseases. Genetic diseases can be life-threatening, often manifesting early in life. Approximately 8% of births in SA are affected, and more common genetic diseases, such as metabolic disease and cancer, manifest later in life in up to 20% of the population. This represents a massive healthcare burden to SA hospitals. The number of genetic disorders in the human population ranges from 7000 to 8000, over 3000 of which are caused by unknown mutations. In 2013, SA initiated the Saudi Human Genome Program (SHGP), which aims to sequence over 100,000 human genomes, with the goal of identifying strategies to discover, prevent, diagnose and treat genetic disorders through precision therapy. High-technology genomics and informatic-based centers that exploit next-generation sequencing (NGS) have now identified mutations underlying many unexplained diseases.


Assuntos
Genoma Humano , Medicina de Precisão/métodos , Análise de Sequência de DNA/métodos , Doenças Autoimunes/genética , Doenças do Sistema Nervoso Central/genética , Anormalidades Congênitas/genética , Consanguinidade , Feminino , Genômica , Humanos , Deficiência Intelectual/genética , Nefropatias/genética , Deformidades Congênitas dos Membros/genética , Masculino , Mutação , Síndromes Neoplásicas Hereditárias/genética , Arábia Saudita
11.
Zhonghua Fu Chan Ke Za Zhi ; 54(2): 87-92, 2019 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-30803166

RESUMO

Objective: To analyze the clinical characteristics of structural malformations in one of monochorionic diamnionic twins (MCDA). Methods: The clinical data of 77 MCDA patients with structural malformations diagnosed by ultrasound were retrospectively reviewed from January 2012 to May 2017. The distribution of structural malformations, prenatal chromosomal karyotyping and pregnancy outcomes were analyzed. Results: (1)Among the 77 MCDA patients with structural malformations, the single malformation accounted for 79%(61/77), the multiple malformations accounted for 21%(16/77). And there were a total of 94 types of malformations, the top three malformations were neurological malformations (32%, 30/94), cardiovascular malformations (29%, 27/94) and twin reversed arterial perfusion sequence (TRAPS;10%,9/94).(2)Among the 77 patients with structural malformation, 64 cases (83%, 64/77) were examined for fetal chromosomes, of whom 14 cases (22%,14/64) were examined for fetal chromosomes of both twins, with 1 case (1/14) of discordant fetal chromosome. (3)Among the 77 patients, 4 cases (5%, 4/77) with severe fetal malformations terminated pregnancy. Totally 29 cases (38%,29/77) with severe malformations were treated with selective fetal reduction, among whom 7 cases (24%, 7/29) experienced unexplained fetal death within 24 hours after the operation; 2 cases (7%, 2/29) happened inevitable abortion, and 2 cases (7%, 2/29) underwent unexplained fetal death during the late pregnancy. Of the remaining 44 patients (57%,44/77) with expectant treatment, 13 cases (30%,13/44) occurred twin transfusion syndrome (Ⅱ-Ⅳ), and were treated with fetoscopic laser occlusion. Eight patients had 2 survival twins, 4 patients delivered 1 survival twin, and 1 patient had dead twins. Conclusions: The most common malformations in MCDA twins are the nervous malformations, cardiovascular malformations and TRAPS. The chromosome karyotype of MCDA twins with structural malformations are sometimes discordant, and separate samling of the twins is suggested for prenatal diagnosis. Selective fetal reduction could be given to severe structural malformation in MCDA patients safely and effectively. For non-severe structural malformation in MCDA patients with twin transfusion syndrome, fetoscopic laser occlusion is safe and effective.


Assuntos
Transtornos Cromossômicos/genética , Anormalidades Congênitas/genética , Doenças em Gêmeos/genética , Transfusão Feto-Fetal , Gravidez de Gêmeos , Gêmeos Monozigóticos/genética , Gêmeos/genética , Transtornos Cromossômicos/diagnóstico , Doenças em Gêmeos/diagnóstico , Feminino , Fetoscopia , Humanos , Cariotipagem , Gravidez , Gravidez de Gêmeos/genética , Gravidez de Gêmeos/fisiologia , Gravidez de Gêmeos/estatística & dados numéricos , Diagnóstico Pré-Natal , Estudos Retrospectivos , Ultrassonografia Pré-Natal
12.
Lancet ; 393(10173): 747-757, 2019 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-30712880

RESUMO

BACKGROUND: Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). METHODS: In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. FINDINGS: The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4-11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). INTERPRETATION: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. FUNDING: UK Department of Health and Social Care and The Wellcome Trust.


Assuntos
Cariótipo Anormal/estatística & dados numéricos , Anormalidades Congênitas/genética , Desenvolvimento Fetal/genética , Feto/anormalidades , Sequenciamento Completo do Exoma/estatística & dados numéricos , Cariótipo Anormal/embriologia , Aborto Eugênico/estatística & dados numéricos , Aborto Espontâneo/epidemiologia , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/epidemiologia , Variações do Número de Cópias de DNA/genética , Feminino , Feto/diagnóstico por imagem , Humanos , Recém-Nascido , Nascimento Vivo/epidemiologia , Masculino , Medição da Translucência Nucal , Pais , Morte Perinatal/etiologia , Gravidez , Estudos Prospectivos , Natimorto/epidemiologia , Sequenciamento Completo do Exoma/métodos
14.
Sex Dev ; 13(1): 35-40, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30739119

RESUMO

Müllerian anomalies comprise the Mayer-Rokitansky-Küster-Hauser syndrome as well as fusion defects of the müllerian ducts. Recurrent micro-aberrations like deletions in 16p11.2 encompassing TBX6 were found to be causative in these patients. TBX6 encodes a transcription factor which plays a role in paraxial mesoderm differentiation/specification. In previous studies, we and other groups found possibly pathogenic variants in TBX6 in patients with müllerian anomalies. Since we suggested TBX6 as a strong candidate, we performed sequential analysis of the TBX6 gene in additional 125 patients with müllerian anomalies, and 2 possibly pathogenic missense variants and 1 nonsense substitution in TBX6 in 4/125 patients were found. The missense variant c.484G>A, which we have described in a previous study, was reidentified but with no higher frequency as in our controls. We detected 3 possibly pathogenic variants in TBX6 and could show that the variant c.484G>A is not causative for disorders of the müllerian ducts in the non-Finnish European population. In summary, we present increasing evidence for association of variants in TBX6 with malformations of the müllerian ducts.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Predisposição Genética para Doença , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/patologia , Mutação/genética , Proteínas com Domínio T/genética , Sequência de Bases , Estudos de Casos e Controles , Feminino , Humanos
15.
Mil Med Res ; 6(1): 4, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30760330

RESUMO

BACKGROUND: Zinner syndrome represents a rare congenital malformation of the urinary tract. It comprises a constellation of Wolffian duct anomalies and is almost exclusively encountered as a classic triad of seminal vesicle cysts, ejaculatory duct obstruction and renal agenesis. Patients can be either asymptomatic or symptomatic. Recently, minimally invasive surgical techniques have emerged, superseding traditional surgery for select symptomatic cases. Our case highlights the finding of a rare clinical syndrome that was incidentally detected during a routine mass screening of military recruits in the Greek Armed Forces. CASE PRESENTATION: Herein, we present a case of a 19-year-old male who reported having a solitary right kidney when examined in a military training center of Northern Greece. No additional clinical information was available; thus, referral to a tertiary urology department for further investigation ensued. Imaging studies, namely, computed tomography and magnetic resonance imaging, revealed left renal aplasia, multiple left seminal vesicle cysts, and ejaculatory duct obstruction. Laboratory values and urinalysis were within normal range. Semen analysis was significant for cryptozoospermia. Our patient remained asymptomatic during the entire hospitalization. Long-term follow-up was recommended. Nevertheless, he declined further investigation and sought treatment in a private practice setting. CONCLUSIONS: This article aims to present the incidental diagnosis of a rare syndrome in a military setting. Population screening conducted in the armed forces permits the identification of undiagnosed diseases that warrant further investigation. To the best of our knowledge, this was the first report of Zinner syndrome in a military recruit and the second case cited of a Greek patient in the published literature. Regular follow-up is the key to timely intervention in conservatively managed cases.


Assuntos
Militares , Glândulas Seminais/anormalidades , Anormalidades Urogenitais/complicações , Anormalidades Congênitas/genética , Anormalidades Congênitas/fisiopatologia , Grécia , Humanos , Achados Incidentais , Rim/anormalidades , Rim/fisiopatologia , Masculino , Análise do Sêmen , Rim Único/complicações , Rim Único/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/etiologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/fisiopatologia , Adulto Jovem
16.
Schweiz Arch Tierheilkd ; 161(1): 59-64, 2019 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-30602432

RESUMO

INTRODUCTION: Congenital deformities of the limbs occur sporadically in various species, but the cause is often unclear. The clinically healthy female Brown Swiss calf presented here showed a congenital peromelia of the left hind limb. The affected limb is twisted, disproportional and the bones distally of the metatarsus are missing. Karyotyping and genome sequencing did not indicate on a genetic cause of the anomaly. An infection with the Schmallenberg virus could not be ruled out. Furthermore, there was no evidence of further adverse environmental effects during pregnancy.


Assuntos
Bovinos/anormalidades , Membro Posterior/anormalidades , Ossos do Metatarso/anormalidades , Animais , Infecções por Bunyaviridae/complicações , Infecções por Bunyaviridae/veterinária , Bovinos/genética , Anormalidades Congênitas/genética , Anormalidades Congênitas/veterinária , Anormalidades Congênitas/virologia , Feminino , Cariometria/veterinária , Orthobunyavirus , Gravidez , Complicações Infecciosas na Gravidez/veterinária , Complicações Infecciosas na Gravidez/virologia
17.
Blood ; 133(10): 1060-1070, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30670449

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood. It is classified as an overlap myeloproliferative/myelodysplastic neoplasm by the World Health Organization and shares some features with chronic myelomonocytic leukemia in adults. JMML pathobiology is characterized by constitutive activation of the Ras signal transduction pathway. About 90% of patients harbor molecular alterations in 1 of 5 genes (PTPN11, NRAS, KRAS, NF1, or CBL), which define genetically and clinically distinct subtypes. Three of these subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in nonsyndromic children, whereas 2 subtypes, JMML in neurofibromatosis type 1 and JMML in children with CBL syndrome, are defined by germline Ras disease and acquired biallelic inactivation of the respective genes in hematopoietic cells. The clinical course of the disease varies widely and can in part be predicted by age, level of hemoglobin F, and platelet count. The majority of children require allogeneic hematopoietic stem cell transplantation for long-term leukemia-free survival, but the disease will eventually resolve spontaneously in ∼15% of patients, rendering the prospective identification of these cases a clinical necessity. Most recently, genome-wide DNA methylation profiles identified distinct methylation signatures correlating with clinical and genetic features and highly predictive for outcome. Understanding the genomic and epigenomic basis of JMML will not only greatly improve precise decision making but also be fundamental for drug development and future collaborative trials.


Assuntos
GTP Fosfo-Hidrolases/genética , Leucemia Mielomonocítica Juvenil/genética , Proteínas de Membrana/genética , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Alelos , Criança , Pré-Escolar , Anormalidades Congênitas/genética , Metilação de DNA , Intervalo Livre de Doença , Epigenômica , Transplante de Células-Tronco Hematopoéticas , Heterozigoto , Humanos , Leucemia Mielomonocítica Juvenil/complicações , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Transdução de Sinais , Síndrome , Transplante Homólogo , Resultado do Tratamento
18.
Congenit Anom (Kyoto) ; 59(3): 74-80, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30554442

RESUMO

Development of external genitalia and perineum is the subject of developmental biology as well as toxicology and teratology researches. Cloaca forms in the lower (caudal) end of endoderm. Such endodermal epithelia and surrounding mesenchyme interact with various signals to form the external genitalia. External genitalia (the anlage termed as genital tubercle: GT) formation shows prominent sexually dimorphic morphogenesis in late embryonic stages, which is an unexplored developmental research field because of many reasons. External genitalia develop adjacent to the cloaca which develops urethra and corporal bodies. Developmental regulators including growth factor signals are necessary for epithelia-mesenchyme interaction (EMI) in posterior embryos including the cloaca and urethra in the genitalia. In the case of male type urethra, formation of tubular urethra proceeds from the lower (ventral) side of external genitalia as a masculinization process in contrast to the case of female urethra. Mechanisms for its development are not elucidated yet due to the lack of suitable mutant mouse models. Because of the recent progresses of Cre (recombinase)-mediated conditional target gene modification analyses, many developmental regulatory genes become increasingly analyzed. Conditional gene knockout mouse approaches and tissue lineage approaches are expected to offer vital information for such sexually dimorphic developmental processes. This review aims to offer recent updates on the progresses of these emerging developmental processes for the research field of congenital anomalies.


Assuntos
Anormalidades Congênitas/genética , Regulação da Expressão Gênica no Desenvolvimento , Genitália/embriologia , Organogênese/genética , Períneo/embriologia , Animais , Anormalidades Congênitas/metabolismo , Anormalidades Congênitas/patologia , Modelos Animais de Doenças , Embrião de Mamíferos , Endoderma/crescimento & desenvolvimento , Endoderma/metabolismo , Endoderma/patologia , Feminino , Genitália/metabolismo , Genitália/patologia , Humanos , Fator de Transcrição MafB/genética , Fator de Transcrição MafB/metabolismo , Masculino , Camundongos , Camundongos Knockout , Períneo/patologia , Caracteres Sexuais , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Via de Sinalização Wnt
19.
Zhonghua Fu Chan Ke Za Zhi ; 53(7): 464-470, 2018 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-30078256

RESUMO

Objective: To investigate the value of single nucleotide polymorphism array (SNP-array) for fetuses with abnormal ultrasound findings. Method: A total of 904 fetuses with abnormal ultrasound findings were enrolled in this study from May 2015 to November 2017, and 434 (48.0%) cases received conventional karyotyping analysis at the same time. According to different abnormal ultrasound category, 904 cases were divided into 5 groups: 280 cases (31.0%) in single system structural anomalies, 31 cases (3.4%) in multiple system structural anomalies, 331 cases (36.6%) in single ultrasound soft marker abnormalities without structural anomalies, 107 cases (11.8%) in multiple soft marker abnormalities and 155 cases (17.2%) in structural abnormalities combined with soft markers abnormalities. Abnormal detection rates by SNP-array among 5 groups of abnormal ultrasound category were calculated. Result: (1) Total SNP-array results: 171 (19.0%) cases out of 904 cases analyzed by SNP-array, presented chromosomal abnormalities. Pathogenic copy number variants were detected in 27 cases (3.0%) and variants of unknown significance were detected in 81 cases (7.8%) . In addition, 7 cases (26.0%) were found with new mutation by parental validation. (2) SNP-array of 5 groups: among the 5 groups of abnormal ultrasound category, chromosomal abnormalities were identified by SNP-array in 19.3% (54/280) with single system structural abnormalities, 25.8% (8/31) with multiple system structural abnormalities, 13.9% (46/331) with single nonstructural anomalies, 19.6% (21/107) with multiple nonstructural anomalies and 27.1% (42/155) with structural abnormalities combined with nonstructural anomalies. The differences were significant (P=0.010) . No chromosome abnormalities was identified in single soft marker abnormalities, such as choroid plexus cysts, echogenic foci in the heart, single umbilical artery and pyelectasis. (3) Chromosomal abnormalities: the abnormal detection rate of aneuploidy chromosomal abnormalities by SNP-array increased with the maternal age, decreased with the gestational weeks (all P<0.05) . However, the pathogenic copy number variants and variants of unknown significance rates did not change with maternal age and gestational weeks (all P>0.05) . (4) SNP-array and karyotyping: 434 cases were analyzed by conventional karyotyping and SNP-array respectively, 10.3% (43/419) of which presented chromosomal abnormalities by conventional karyotyping and 18.7% (81/434) of which presented chromosomal abnormalities by SNP-array. Conclusions: SNP-array could be a useful genetic analysis method in prenatal diagnosis for fetuses with abnormal ultrasound findings. For different abnormal ultrasound category, SNP-array has different detection rate. Compared with conventional karyotyping analysis, SNP-array can improve the detection rates for chromosomal abnormalities and find the chromosome abnormalities which can't be detected by conventional karyotyping analysis. In clinical prenatal genetic counseling, SNP-array should be selected rationally in combination with the various abnormal ultrasound category.


Assuntos
Anormalidades Múltiplas/genética , Transtornos Cromossômicos/genética , Anormalidades Congênitas/genética , Variações do Número de Cópias de DNA , Cariotipagem/métodos , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único , Diagnóstico Pré-Natal/métodos , Ultrassonografia Pré-Natal/métodos , Anormalidades Múltiplas/diagnóstico por imagem , Aneuploidia , Aberrações Cromossômicas , Anormalidades Congênitas/diagnóstico por imagem , Feminino , Feto , Aconselhamento Genético , Testes Genéticos , Humanos , Idade Materna , Gravidez
20.
Bratisl Lek Listy ; 119(6): 330-334, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29947231

RESUMO

AIM: The purpose of this study was to monitor the association between single umbilical artery (SUA), chromosomal abnormalities and associated anomalies during the routine examination of spontaneous or induced miscarriages and premature births. METHODS: During 1992-2015 we morphologically and cytogenetically examined a series of 4098 samples. For 1330 cases the number of umbilical cord vessels could be reported. RESULTS: The presence of single umbilical artery was identified in 67 fetuses of 1330 pregnancies (5.04 %); 36 of the 67 fetuses (53.7 %) had additional congenital malformations. The cultures were unsuccessful in 29 of 67 cases (43.3 %). 38 cases (56.7 %) were successfully karyotyped; 20 out of them had a normal karyotype and 18 had chromosomal anomalies including trisomy 18 (n = 4), trisomy 13 (n = 3), trisomy 21 (n = 2), trisomy 11 (n = 1), triploidy (n = 3), monosomy X (n = 3) and structural chromosomal aberrations (n = 2). CONCLUSION: Isolated SUA is not at increased risk of chromosomal abnormalities and generally does not endanger pregnancy. All chromosomally abnormal embryos and fetuses had associated congenital anomalies. The most frequently associated congenital anomalies were in the musculoskeletal system, central nervous system and genitourinary tract (Tab. 4, Ref. 44).


Assuntos
Aborto Induzido , Aborto Espontâneo/genética , Aberrações Cromossômicas , Anormalidades Congênitas/genética , Cariotipagem , Artéria Umbilical Única/genética , Adulto , Aberrações Cromossômicas/estatística & dados numéricos , Anormalidades Congênitas/epidemiologia , Feminino , Humanos , Recém-Nascido , Trabalho de Parto Prematuro/epidemiologia , Trabalho de Parto Prematuro/genética , Vigilância da População , Gravidez , Artéria Umbilical Única/epidemiologia , Eslováquia , Estatística como Assunto
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