RESUMO
OBJECTIVE: This document addresses the clinical application of next-generation sequencing (NGS) technologies for prenatal genetic diagnosis and aims to establish clinical practice recommendations in Spain to ensure uniformity in implementing these technologies into prenatal care. METHODS: A joint committee of expert obstetricians and geneticists was created to review the existing literature on fetal NGS for genetic diagnosis and to make recommendations for Spanish healthcare professionals. RESULTS: This guideline summarises technical aspects of NGS technologies, clinical indications in prenatal setting, considerations regarding findings to be reported, genetic counselling considerations as well as data storage and protection policies. CONCLUSIONS: This document provides updated recommendations for the use of NGS diagnostic tests in prenatal diagnosis. These recommendations should be periodically reviewed as our knowledge of the clinical utility of NGS technologies, applied during pregnancy, may advance.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Diagnóstico Pré-Natal , Humanos , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/normas , Gravidez , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Feminino , Espanha , Testes Genéticos/métodos , Testes Genéticos/normas , Aconselhamento Genético/métodos , Aconselhamento Genético/normas , Obstetrícia/normas , Obstetrícia/métodos , Ginecologia/normasRESUMO
At 16 + 6-weeks a fetal scan performed in the second pregnancy of a 42 y.o. woman identified a right multicystic dysplastic kidney, left renal agenesis, absent urinary bladder, myocardial hypertrophy, increased nuchal fold, a single umbilical artery, and oligohydramnios. Trio exome sequencing analysis detected a novel pathogenic NONO variant. Postmortem examination after the termination of pregnancy confirmed the ultrasound findings and also revealed pulmonary hypoplasia, retrognathia and low-set ears. The variant was a novel de novo hemizygous pathogenic loss-of-function variant in NONO [NM_007363.5], associated with a rare X-linked recessive neurodevelopmental disorder, named intellectual developmental disorder, X-linked syndromic 34 (OMIM#300967). The postnatal characteristic features of this disorder include intellectual disability, developmental delay, macrocephaly, structural abnormalities involving the corpus callosum and/or cerebellum, left ventricular noncompaction and other congenital heart defects. In the prenatal setting, the phenotype has been poorly described, with all described cases presenting with heart defects. This case highlights the need of further clinical delineation to include renal abnormalities in the prenatal phenotype spectrum.
Assuntos
Cardiopatias Congênitas , Deficiência Intelectual , Nefropatias , Anormalidades Urogenitais , Gravidez , Feminino , Humanos , Rim/diagnóstico por imagem , Rim/anormalidades , Feto/anormalidades , Nefropatias/diagnóstico por imagem , Nefropatias/genética , Deficiência Intelectual/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a RNA/genéticaRESUMO
BACKGROUND & AIMS: Transcription co-activator factor 20 (TCF20) is a regulator of transcription factors involved in extracellular matrix remodelling. In addition, TCF20 genomic variants in humans have been associated with impaired intellectual disability. Therefore, we hypothesized that TCF20 has several functions beyond those described in neurogenesis, including the regulation of fibrogenesis. METHODS: Tcf20 knock-out (Tcf20-/- ) and Tcf20 heterozygous mice were generated by homologous recombination. TCF20 gene genotyping and expression was assessed in patients with pathogenic variants in the TCF20 gene. Neural development was investigated by immufluorescense. Mitochondrial metabolic activity was evaluated with the Seahorse analyser. The proteome analysis was carried out by gas chromatography mass-spectrometry. RESULTS: Characterization of Tcf20-/- newborn mice showed impaired neural development and death after birth. In contrast, heterozygous mice were viable but showed higher CCl4 -induced liver fibrosis and a differential expression of genes involved in extracellular matrix homeostasis compared to wild-type mice, along with abnormal behavioural patterns compatible with autism-like phenotypes. Tcf20-/- embryonic livers and mouse embryonic fibroblast (MEF) cells revealed differential expression of structural proteins involved in the mitochondrial oxidative phosphorylation chain, increased rates of mitochondrial metabolic activity and alterations in metabolites of the citric acid cycle. These results parallel to those found in patients with TCF20 pathogenic variants, including alterations of the fibrosis scores (ELF and APRI) and the elevation of succinate concentration in plasma. CONCLUSIONS: We demonstrated a new role of Tcf20 in fibrogenesis and mitochondria metabolism in mice and showed the association of TCF20 deficiency with fibrosis and metabolic biomarkers in humans.
Assuntos
Fibroblastos , Fígado , Humanos , Camundongos , Animais , Fibroblastos/patologia , Fígado/patologia , Cirrose Hepática/patologia , Mitocôndrias/patologia , Fatores de Transcrição/genéticaRESUMO
INTRODUCTION: The introduction of prenatal cell-free DNA as a screening test has surpassed traditional combined first-trimester screening (cFTS) in the detection of common trisomies. However, its current limitation in detecting only common trisomies is affecting the diagnostic yield for other clinically significant chromosomal abnormalities. METHODS: In efforts to optimize the detection of fetuses with genetic abnormalities, we have analyzed the relationship between the cFTS risk score and biomarkers with atypical chromosomal abnormalities. Furthermore, we have evaluated the impact of prenatal cell-free DNA screening on the detection of chromosomal abnormalities in our population. For these purposes, we performed a retrospective study of 877 singleton pregnancies who underwent chromosomal microarray analysis (CMA) between 2013 and 2020 and for whom cFTS data were available. RESULTS: The results demonstrated that low levels of free beta-human chorionic gonadotropin (ß-hCG) (≤0.37 multiples of the median) and increased fetal nuchal translucency (NT) (≥3.5 mm) were statistically associated with the presence of atypical chromosomal abnormalities. In fact, the risk of pathogenic CMA results increased from 6 to 10% when fetal NT was increased and from 6 to 20% when a low serum ß-hCG level was detected in the high-risk cFTS group. Moreover, our results showed that altered serum levels of ß-hCG can have a substantial impact on the early detection of clinically relevant copy number variants. DISCUSSION/CONCLUSION: Traditional cFTS can potentially identify a substantial proportion of atypical chromosomal aberrations, and women with increased NT or low maternal serum ß-hCG levels are at increased risk of having pathogenic CMA results. Our results may help clinicians and women decide whether invasive testing or prenatal cell-free DNA screening testing is more appropriate for each situation.
Assuntos
Gonadotropina Coriônica Humana Subunidade beta , Síndrome de Down , Gonadotropina Coriônica Humana Subunidade beta/sangue , Aberrações Cromossômicas , Síndrome de Down/diagnóstico , Síndrome de Down/epidemiologia , Síndrome de Down/genética , Feminino , Humanos , Medição da Translucência Nucal , Gravidez , Primeiro Trimestre da Gravidez , Proteína Plasmática A Associada à Gravidez , Diagnóstico Pré-Natal/métodos , Estudos RetrospectivosRESUMO
Chromosomal microarray analysis (CMA) has now replaced karyotyping in the analysis of prenatal cases with a fetal structural anomaly, whereas in those pregnancies undergoing invasive prenatal diagnosis with a normal fetal ultrasound, conventional karyotyping is still performed. The aims of this study were to establish the diagnostic yield of CMA in prenatal diagnosis, and to provide new data that might contribute to reconsider current practices. We reviewed 2905 prenatal samples with a normal rapid aneuploidy detection test referred for evaluation by CMA testing. Our study revealed pathogenic and reported susceptibility copy number variants associated with syndromic disorders in 4.8% (n = 138/2905) of cases, being 2.8% (n = 81/2905) the estimated added diagnostic value of CMA over karyotyping. Clinically significant CMA abnormality was detected in 5.4% (107/1975) of the fetuses with ultrasound anomalies and in 1.4% (5/345) of those considered as low-risk pregnancies. Our series shows that in prenatal samples, CMA increases 2-fold the diagnostic yield achieved by conventional karyotyping.
Assuntos
Cromossomos/genética , Doenças Genéticas Inatas/genética , Testes Genéticos , Diagnóstico Pré-Natal , Aneuploidia , Variações do Número de Cópias de DNA/genética , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Humanos , Análise em Microsséries/tendências , Gravidez , SíndromeRESUMO
OBJECTIVE: To perform a systematic review of the literature and a meta-analysis to estimate the incremental yield of chromosomal microarray analysis (CMA) over karyotyping in fetal growth restriction (FGR). METHODS: This was a systematic review conducted in accordance with the PRISMA criteria. All articles identified in PubMed, Ovid Medline, and ISI Web of Knowledge (Web of Science) from January 2009 to November 2016 describing pathogenic copy number variants (CNVs) in fetuses with growth restriction were included. Case reports were excluded. Risk differences were pooled to estimate the overall and stratified CMA incremental yield. RESULTS: Ten studies with full data available met the inclusion criteria for analysis. Combined data from these studies revealed a 4% (95% confidence interval [CI] 1-6%) incremental yield of CMA over karyotyping in nonmalformed growth-restricted fetuses, and a 10% (95% CI 6-14%) incremental yield in FGR when associated with fetal malformations. The most frequently found pathogenic CNVs were 22q11.2 duplication, Xp22.3 deletion, and 7q11.23 deletion (Williams-Beuren syndrome), particularly in isolated FGR. CONCLUSION: The use of genomic CMA provides a 4% incremental yield of detecting pathogenic CNVs in fetuses with isolated growth restriction and normal karyotype.
Assuntos
Variações do Número de Cópias de DNA , Retardo do Crescimento Fetal/genética , Cariotipagem , Análise em Microsséries , Diagnóstico Pré-Natal , Feminino , Humanos , GravidezRESUMO
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and autism. In most of cases, the molecular basis of this syndrome is a CGG repeat expansion in the 5' untranslated region of the FMR1 gene. It is inherited as an X linked dominant trait, with a reduced penetrance (80% for males and 30% for females). Full mutation (FM) expansion from premutated alleles (PM) is only acquired via maternal meiosis, while paternal transmission always remains in the PM range. We present a 16-year-old girl with a mild fragile X syndrome phenotype. FMR1 gene study showed that the patient inherited a mosaic premutation-full mutation with an unmethylated uninterrupted allele (175, >200 CGG) from her father. The father showed an 88 CGG uninterrupted unmethylated allele in blood and sperm cells. To our knowledge, this is the first case of a FMR1 mosaic premutation-full mutation allele inherited from a PM father. In our opinion, the most likely explanation could be a postzygotic somatic expansion. We can conclude that in rare cases of a child with a full mutation whose mother does not carry a premutation, the possibility of paternal transmission should be considered.
Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Mutação , Herança Paterna , Adolescente , Adulto , Feminino , Síndrome do Cromossomo X Frágil/patologia , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: Little information is available about the risk of microdeletion and microduplication syndromes in fetal growth restriction (FGR) with a normal karyotype. OBJECTIVE: To assess the incremental yield of genomic microarray over conventional karyotyping in fetuses with early growth restriction. STUDY DESIGN: Genomic microarray was prospectively performed in fetuses with early growth restriction defined as a fetal weight below the 3rd percentile estimated before 32 weeks of pregnancy, and a normal quantitative fluorescent polymerase chain reaction result. The incremental yield of genomic microarray was defined by the rate of fetuses presenting with a pathogenic copy number variant below 10 Mb. RESULTS: Among 133 fetuses with early FGR, a 6.8% (95% CI: 2.5-11.0) incremental yield of genomic microarray over karyotyping was observed. This incremental yield was 4.8% (95% CI: 0.2-9.3) in isolated FGR, 10% (95% CI: 0-20.7) in FGR with nonstructural anomalies, and 10.5% (95% CI: 0-24.3) in FGR with structural anomalies. CONCLUSION: Our multicenter study reveals that 6.8% of fetuses with early growth restriction present with submicroscopic anomalies after common aneuploidies were excluded. Even when FGR is observed as an isolated finding, genomic microarray analysis should be considered after or instead of karyotyping, due to its 4.8% incremental yield.
Assuntos
Retardo do Crescimento Fetal/genética , Aberrações Cromossômicas , Feminino , Desenvolvimento Fetal/genética , Genômica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Resultado da GravidezRESUMO
The wide spectrum of clinical phenotypes associated with the FMR1 premutation affect more than two million people worldwide. The clinical implications have only been recognized recently despite this disorder constitutes a relevant health problem. The present issue of The Cerebellum is focused on the "2(nd) International Conference on the FMR1 Premutation: Basic Mechanisms and Clinical Involvement" held in Sitges, Barcelona (Spain), from September 30th to October 2nd, 2015. The conference was attended by professionals from different countries in Europe, the USA, Chile, Israel, Australia, and Indonesia and covered the latest clinical and molecular findings resulting from FMR1 premutation studies. Although the pathologies associated with the FMR1 premutation are considered as rare diseases, seventy abstracts were presented. This reflects the relevance of this topic in the medical community and the growing interest among professionals from other disciplines. The major topics discussed included why and how the mRNA toxicity due to a gain of function and non-canonical RAN are responsible for disorders associated with the premutation. Several presentations addressed the impact of these mechanisms in FXTAS and FXPOI, two clinical presentations caused by the FMR1 premutation. Interestingly, a deterioration of the DNA repair machinery was first proposed as the pathogenicity cause of premutation alleles. Communications related to FXTAS and FXPOI animal models were also presented. These models facilitate studies aimed to understand disease progression and early treatment interventions. Finally, there were presentations related to psychiatric, psychological, neurological, and radiological aspects. Interesting discussion on intermediate alleles and their involvement in clinical and reproductive aspects was generated. In this regards, genetic counselling is improved by taking into account the AGG interruptions and including information about the FMR1 premutation associated pathologies although there are still some uncertainties linked to the spectrum of these pathologies. Overall, the meeting covered all aspects of the different pathologies associated with the premutation of the FMR1 gene.
Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Animais , Congressos como Assunto , Humanos , EspanhaRESUMO
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that occurs in FMR1 premutation carriers. The prevalence of FMR1 premutation carriers in the general population is relatively high, and although rare, a premutation in both X chromosomes may occur in females inheriting a premutation allele from each of both parent carriers. Here, we report the first female with an autozygous (homozygous by descendent) FMR1 premutation allele, who fulfills neurological and radiological FXTAS findings/criteria. Molecular characterization included CGG repeat length, AGG interruption pattern, FMR1 messenger RNA (mRNA), fragile X mental retardation protein (FMRP) level quantification, and single-nucleotide polymorphism (SNP) microarray. Neuroradiological assessment of 3-T magnetic resonance imaging and neurological and cognitive/neuropsychological evaluations were performed. Neurological and neuroradiological examination of the female with the same FMR1 allele in the premutation range (77 CGGs) demonstrated FXTAS features. Further familial evaluation showed a similar neuropsychiatric profile, with impairments in cognitive flexibility and visuospatial function, mainly. A unique family with an autozygous FMR1 premutation female is presented. Neurological/cognitive and neuroradiological examinations revealed FXTAS-specific findings in the female with the autozygous FMR1 premutation allele. The consistent molecular and cognitive/psychiatric phenotype in family members suggests that carrying one or two FMR1 premutation alleles has no effect on illness severity.
Assuntos
Ataxia/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Dosagem de Genes , Tremor/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Ataxia/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Família , Feminino , Síndrome do Cromossomo X Frágil/diagnóstico por imagem , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Tremor/diagnóstico por imagemRESUMO
BACKGROUND: Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a late-onset multisystem neurological disorder characterized by intention tremor and cerebellar ataxia. OBJECTIVE: We hypothesized that in FMR1 premutation females with FXTAS, a normal X chromosome might more frequently be inactivated; therefore, the aim of this study was to determine the relationship between skewed X chromosome inactivation (XCI) and FXTAS. METHODS: We studied the XCI patterns of cases of FMR1 premutation in 10 women with FXTAS and 21 without FXTAS. RESULTS: The distribution of XCI patterns in the FXTAS and no-FXTAS groups showed differences regarding the allele presenting severe skewed XCI. In the FXTAS group, all cases preferentially inactivated the non-expanded X chromosome, whereas in the no-FXTAS group, all inactivated the expanded X chromosome. Nevertheless, no significant differences were found on comparing XCI frequencies among FMR1 premutation carriers with and without FXTAS. As expected, we found statistically significant differences in the skewed XCI on comparing FMR1 premutation women and controls. CONCLUSION: Although the reduced sample size and blood XCI patterns are two limitations of this study, our results suggest that the skewed XCI of the normal FMR1 allele may be a risk factor for the development of FXTAS. Furthermore, our findings also support the protective effect of the expression of a normal FMR1 allele.
Assuntos
Ataxia/sangue , Ataxia/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/sangue , Síndrome do Cromossomo X Frágil/genética , Tremor/sangue , Tremor/genética , Inativação do Cromossomo X , Análise Química do Sangue , Metilação de DNA , Análise Mutacional de DNA , Feminino , Heterozigoto , Humanos , Pessoa de Meia-IdadeRESUMO
Male premutation carriers presenting between 55 and 200 CGG repeats in the Fragile-X-associated (FMR1) gene are at risk of developing Fragile X Tremor/Ataxia Syndrome (FXTAS), and females undergo Premature Ovarian Failure (POF1). Here, we have evaluated gene expression profiles from blood in male FMR1 premutation carriers and detected a strong deregulation of genes enriched in FXTAS relevant biological pathways, including inflammation, neuronal homeostasis and viability. Gene expression profiling distinguished between control individuals, carriers with FXTAS and carriers without FXTAS, with levels of expanded FMR1 mRNA being increased in FXTAS patients. In vitro studies in a neuronal cell model indicate that expression levels of expanded FMR1 5'-UTR are relevant in modulating the transcriptome. Thus, perturbations of the transcriptome may be an interplay between the CGG expansion size and FMR1 expression levels. Several deregulated genes (DFFA, BCL2L11, BCL2L1, APP, SOD1, RNF10, HDAC5, KCNC3, ATXN7, ATXN3 and EAP1) were validated in brain samples of a FXTAS mouse model. Downregulation of EAP1, a gene involved in the female reproductive system physiology, was confirmed in female carriers. Decreased levels were detected in female carriers with POF1 compared to those without POF1, suggesting that EAP1 levels contribute to ovarian insufficiency. In summary, gene expression profiling in blood has uncovered mechanisms that may underlie different pathological aspects of the premutation. A better understanding of the transcriptome dynamics in relation with expanded FMR1 mRNA expression levels and CGG expansion size may provide mechanistic insights into the disease process and a more accurate FXTAS diagnosis to the myriad of phenotypes associated with the premutation.
Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Regulação da Expressão Gênica/genética , Infertilidade/genética , Doenças Neurodegenerativas/sangue , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Análise em Microsséries , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Neuroblastoma/patologia , Doenças Neurodegenerativas/genética , Fenótipo , Proteínas/genética , Proteínas/metabolismo , Securina/genética , Securina/metabolismoRESUMO
FMR1 premutation carriers (55-200 CGG repeats) are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with motor and cognitive impairment. Bilateral hyperintensities of the middle cerebellar peduncles (MCP sign) are the major radiological hallmarks of FXTAS. In the general population, enlarged perivascular spaces (PVS) are biomarkers of small vessel disease and glymphatic dysfunction and are associated with cognitive decline. Our aim was to determine if premutation carriers show higher ratings of PVS than controls and whether enlarged PVS are associated with motor and cognitive impairment, MRI features of neurodegeneration, cerebrovascular risk factors and CGG repeat length. We evaluated 655 MRIs (1-10 visits/participant) from 229 carriers (164 with FXTAS and 65 without FXTAS) and 133 controls. PVS in the basal ganglia (BG-EPVS), centrum semiovale, and midbrain were evaluated with a semiquantitative scale. Mixed-effects models were used for statistical analysis adjusting for age. In carriers with FXTAS, we revealed that (1) BG-PVS ratings were higher than those of controls and carriers without FXTAS; (2) BG-PVS severity was associated with brain atrophy, white matter hyperintensities, enlarged ventricles, FXTAS stage and abnormal gait; (3) age-related increase in BG-PVS was associated with cognitive dysfunction; and (4) PVS ratings of all three regions showed robust associations with CGG repeat length and were higher in carriers with the MCP sign than carriers without the sign. This study demonstrates clinical relevance of PVS in FXTAS especially in the basal ganglia region and suggests microangiopathy and dysfunctional cerebrospinal fluid circulation in FXTAS physiopathology.
Assuntos
Ataxia , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Sistema Glinfático , Imageamento por Ressonância Magnética , Tremor , Humanos , Masculino , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/diagnóstico por imagem , Síndrome do Cromossomo X Frágil/patologia , Pessoa de Meia-Idade , Idoso , Proteína do X Frágil da Deficiência Intelectual/genética , Tremor/genética , Tremor/diagnóstico por imagem , Tremor/patologia , Ataxia/genética , Ataxia/diagnóstico por imagem , Ataxia/patologia , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/patologia , Fatores de Risco , Heterozigoto , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/etiologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
BACKGROUND: Fragile X-associated primary ovarian insufficiency (FXPOI), characterized by amenorrhea before age 40 years, occurs in 20% of female FMR1 premutation carriers. Presently, there are no molecular or biomarkers that can help predicting which FMR1 premutation women will develop FXPOI. We previously demonstrated that high FMR4 levels can discriminate between FMR1 premutation carriers with and without FXPOI. In the present study the relationship between the expression levels of FMR4 and the ovarian reserve markers was assessed in female FMR1 premutation carriers under age of 35 years. METHODS: We examined the association between FMR4 transcript levels and the measures of total antral follicle count (AFC) and serum anti-müllerian hormone (AMH) levels as markers of ovarian follicle reserve. RESULTS: Results revealed a negative association between FMR4 levels and AMH (r = 0.45) and AFC (r = 0.64). Statistically significant higher FMR4 transcript levels were found among those FMR1 premutation women with both, low AFCs and AMH levels. CONCLUSIONS: These findings reinforce previous studies supporting the association between high levels of FMR4 and the risk of developing FXPOI in FMR1 premutation carriers.
Assuntos
Hormônio Antimülleriano , Biomarcadores , Proteína do X Frágil da Deficiência Intelectual , Reserva Ovariana , Insuficiência Ovariana Primária , RNA Longo não Codificante , Adulto , Feminino , Humanos , Adulto Jovem , Hormônio Antimülleriano/sangue , Biomarcadores/sangue , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/sangue , Heterozigoto , Mutação , Folículo Ovariano/metabolismo , Reserva Ovariana/genética , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/sangueRESUMO
PURPOSE: Fragile X-associated tremor/ataxia syndrome is a late-onset neurodegenerative disorder that occurs in FMR1 premutation carriers. It is well known that the apolipoprotein E ε4 allele is a risk factor for neurodegenerative disease. The main goal of this work was to evaluate the apolipoprotein E genotypes and allelic distribution among patients with fragile X-associated tremor/ataxia syndrome. METHODS: A total of 44 unrelated FMR1 premutation carriers (22 presenting with fragile X-associated tremor/ataxia syndrome and 22 without fragile X-associated tremor/ataxia syndrome) were genotyped. RESULTS: All the apolipoprotein E ε4/4 genotype carriers detected (100%), and six of the seven apolipoprotein E ε4/3 genotype carriers (85.7%) are patients presenting with fragile X-associated tremor/ataxia syndrome symptoms, whereas only 40% of the apolipoprotein E ε3/3 genotype carriers belong to the fragile X-associated tremor/ataxia syndrome group. The results showed that the presence of the apolipoprotein E ε4 allele increases the risk of developing fragile X-associated tremor/ataxia syndrome (odds ratio = 12.041; P = 0.034). CONCLUSION: On the basis of these results, we conclude that the presence of at least one apolipoprotein E ε4 allele might act as a genetic factor predisposing individuals to develop fragile X-associated tremor/ataxia syndrome.
Assuntos
Apolipoproteína E3/genética , Apolipoproteína E4/genética , Ataxia/genética , Síndrome do Cromossomo X Frágil/genética , Tremor/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Espanha , População Branca/genéticaRESUMO
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that appears in adult FMR1 premutation carriers. The neuropathological hallmark of FXTAS is an intranuclear inclusion in neurons and astrocytes. Nearly 200 different proteins have been identified in FXTAS inclusions, being the small ubiquitin-related modifier 2 (SUMO2), ubiquitin and p62 the most highly abundant. These proteins are components of the protein degradation machinery. This study aimed to characterize SUMO2/3 expression levels and autophagy process in human postmortem brain samples and skin fibroblast cultures from FXTAS patients. Results revealed that FXTAS postmortem brain samples are positive for SUMO2/3 conjugates and supported the idea that SUMO2/3 accumulation is involved in inclusion formation. Insights from RNA-sequencing data indicated that SUMOylation processes are significantly upregulated in FXTAS samples. In addition, the analysis of the autophagy flux showed the accumulation of p62 protein levels and autophagosomes in skin fibroblasts from FXTAS patients. Similarly, gene set analysis evidenced a significant downregulation in gene ontology terms related to autophagy in FXTAS samples. Overall, this study provides new evidence supporting the role of SUMOylation and autophagic processes in the pathogenic mechanisms underlying FXTAS.
Assuntos
Síndrome do Cromossomo X Frágil , Tremor , Adulto , Humanos , Tremor/genética , Tremor/metabolismo , Tremor/patologia , Ubiquitina/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/patologia , Ataxia/patologia , Autofagia , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismoRESUMO
Neurological disorders (ND) are diseases that affect the brain and the central and autonomic nervous systems, such as neurodevelopmental disorders, cerebellar ataxias, Parkinson's disease, or epilepsies. Nowadays, recommendations of the American College of Medical Genetics and Genomics strongly recommend applying next generation sequencing (NGS) as a first-line test in patients with these disorders. Whole exome sequencing (WES) is widely regarded as the current technology of choice for diagnosing monogenic ND. The introduction of NGS allows for rapid and inexpensive large-scale genomic analysis and has led to enormous progress in deciphering monogenic forms of various genetic diseases. The simultaneous analysis of several potentially mutated genes improves the diagnostic process, making it faster and more efficient. The main aim of this report is to discuss the impact and advantages of the implementation of WES into the clinical diagnosis and management of ND. Therefore, we have performed a retrospective evaluation of WES application in 209 cases referred to the Department of Biochemistry and Molecular Genetics of the Hospital Clinic of Barcelona for WES sequencing derived from neurologists or clinical geneticists. In addition, we have further discussed some important facts regarding classification criteria for pathogenicity of rare variants, variants of unknown significance, deleterious variants, different clinical phenotypes, or frequency of actionable secondary findings. Different studies have shown that WES implementation establish diagnostic rate around 32% in ND and the continuous molecular diagnosis is essential to solve the remaining cases.
Assuntos
Epilepsia , Exoma , Humanos , Sequenciamento do Exoma , Estudos Retrospectivos , Exoma/genética , Fenótipo , Epilepsia/diagnóstico , Epilepsia/genéticaRESUMO
Congenital balanced reciprocal translocations are one of the most frequent structural chromosomal aberrations in the population. We report a familial translocation t(12;22)(p13.3;pter) responsible for intellectual disabilities and congenital anomalies characterized by FISH and array CGH. Two patients carried a der(12)t(12;22)(p13.3;pter), resulting in a 6 Mb 12pter deletion. Patients presented with intellectual disabilities, pre- and post-natal growth retardation, ponderal development delay, global hypotonia, feeding problems and dysmorphic features. Two relatives presented with the reciprocal 12pter duplication, which had no clinical manifestations associated. For this translocation, we propose a mechanism based on a non-allelic recombination model, in which recombination of direct oriented segmental duplications between non-homologous chromatids leads to the reciprocal translocation. The characterization of this translocation has been critical for the family. Translocation carriers have a risk of 40% of having offspring carrying unbalanced products. 12p13.3 deletion carriers present with a recognizable syndrome and on the contrary, 12p13.3 duplication carriers present without clinical manifestations. Other published cases of 12p13.3 duplication show that this syndrome has a variable phenotype. It is advisable to delineate the duplication size and to discard other genetic aberrations, in order to give an accurate genetic counseling in patients carrying 12pter duplications.
Assuntos
Cromossomos Humanos Par 12/genética , Rearranjo Gênico , Deficiência Intelectual/genética , Deleção de Sequência , Família , Humanos , Duplicações Segmentares Genômicas , Translocação GenéticaRESUMO
The deletion of the long arm of chromosome 18 causes a contiguous gene deletion syndrome with a highly variable phenotype, usually related to the extent of the deleted region. The most commonly reported clinical features include: decreased growth, microcephaly, facial abnormalities, hypotonia, developmental delay, intellectual disability, congenital aural atresia with hearing impairment and limb anomalies. Here we report on a familial terminal deletion of 18q23 region transmitted from a mother to two daughters, resulting in a remarkable phenotypic variability. The deletion was first detected by conventional cytogenetic analysis in one daughter and subsequently characterized using fluorescence in situ hybridization (FISH) and array-CGH. FISH analysis using subtelomeric 18p and 18q probes confirmed the 18qter deletion in the three patients, and FISH with a whole chromosome painting probe specific for chromosome 18 excluded rearrangements with other chromosomes. Array-CGH analysis allowed us to precisely define the extent of the deletion, which spans 4.8 Mb from 71,236,891 to 76,093,303 genomic positions and includes GALR1 and MBP genes, among others. High-resolution analysis of the deletion, besides a detailed clinical assessment, has provided important data for phenotype-genotype correlation and genetic counseling in this family. Furthermore, this study adds valuable information for phenotype-genotype correlation in 18q- syndrome and might facilitate future search for candidate genes involved in each phenotypic trait.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 18 , Hormônio do Crescimento/deficiência , Estatura/genética , Criança , Hibridização Genômica Comparativa , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , FenótipoRESUMO
A psychiatric disorder is a mental illness involving significant disturbances in thinking, emotional regulation or behavior [...].