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1.
Obstet Gynecol ; 137(3): 423-429, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33543899

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), uses two primary receptors, type II transmembrane serine protease and angiotensin-converting enzyme-2, for priming and cellular invasion, respectively. Both proteins have been demonstrated to be present in different concentrations in females and males, which may explain a mechanism for the reported higher case-fatality rate in males. Despite the known sex difference in COVID-19 disease mortality, preliminary data suggest there are certain female populations, including pregnant and menopausal women and possibly polycystic ovarian syndrome patients who are more susceptible to COVID-19-related morbidity. This commentary analyzes the interplay between sex differences, hormones, and the immune function in each of these populations with respect to the risk and severity of COVID-19 and proposes biological rationales to explain these differences.


Assuntos
/epidemiologia , Predisposição Genética para Doença , /genética , Cromossomos Humanos X , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Menopausa/fisiologia , Morbidade , Síndrome do Ovário Policístico/epidemiologia , Gravidez , Serina Endopeptidases/genética , Fatores Sexuais
2.
Nat Commun ; 12(1): 627, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504798

RESUMO

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.


Assuntos
Deficiências do Desenvolvimento/genética , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Variação Genética , Cromossomos Humanos X/genética , Feminino , Genes Recessivos , Humanos , Padrões de Herança/genética , Masculino , Herança Multifatorial/genética , Mutação/genética , Fenótipo , Caracteres Sexuais
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(11): 1287-1290, 2020 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-33179242

RESUMO

OBJECTIVE: To explore the pathogenesis and genetic characteristics of a fetus with a der(X)t(X;Y)(p22.3;q11.2) karyotype. METHODS: G-banding karyotyping analysis, BoBs (BACs-on-Beads) assay, and single nucleotide polymorphism array (SNP-array) were used to delineate the structural chromosomal aberration of the fetus. The parents of the fetus were also subjected to karyotyping analysis. RESULTS: The fetus and its mother were both found to have a karyotype of 46,X,add(X)(p22), while the father was normal. BoBs assay indicated that there was a lack of Xp22 but a gain of Yq11 signal. SNP-array confirmed that the fetus and its mother both had a 7.13 Mb deletion at Xp22.33p22.31 (608 021-7 736 547) and gain of a 12.52 Mb fragment at Yq11.221q11.23 (16 271 151-28 788 643). CONCLUSION: The fetus was determined to have a karyotype of 46,X,der(X)t(X;Y)(p22.3;q11.2)mat. The combined use of various methods has facilitated delineation of the fetal chromosomal aberration and prediction of the risk prediction for subsequent pregnancy.


Assuntos
Cromossomos Humanos X , Cromossomos Humanos Y , Diagnóstico Pré-Natal , Bandeamento Cromossômico , Deleção Cromossômica , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Feminino , Feto , Humanos , Cariotipagem , Masculino , Gravidez , Translocação Genética
4.
Science ; 369(6509)2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32913072

RESUMO

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.


Assuntos
Regulação da Expressão Gênica , Expressão Gênica , Caracteres Sexuais , Cromossomos Humanos X/genética , Doença/genética , Epigênese Genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Especificidade de Órgãos , Regiões Promotoras Genéticas , Locos de Características Quantitativas , Fatores Sexuais
5.
Proc Natl Acad Sci U S A ; 117(33): 20063-20069, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747577

RESUMO

In human populations, the relative levels of neutral diversity on the X and autosomes differ markedly from each other and from the naïve theoretical expectation of 3/4. Here we propose an explanation for these differences based on new theory about the effects of sex-specific life history and given pedigree-based estimates of the dependence of human mutation rates on sex and age. We demonstrate that life history effects, particularly longer generation times in males than in females, are expected to have had multiple effects on human X-to-autosome (X:A) diversity ratios, as a result of male-biased mutation rates, the equilibrium X:A ratio of effective population sizes, and the differential responses to changes in population size. We also show that the standard approach of using divergence between species to correct for male mutation bias results in biased estimates of X:A effective population size ratios. We obtain alternative estimates using pedigree-based estimates of the male mutation bias, which reveal that X:A ratios of effective population sizes are considerably greater than previously appreciated. Finally, we find that the joint effects of historical changes in life history and population size can explain the observed X:A diversity ratios in extant human populations. Our results suggest that ancestral human populations were highly polygynous, that non-African populations experienced a substantial reduction in polygyny and/or increase in the male-to-female ratio of generation times around the Out-of-Africa bottleneck, and that current diversity levels were affected by fairly recent changes in sex-specific life history.


Assuntos
Cromossomos Humanos X/genética , Genética Humana , Densidade Demográfica , Biodiversidade , Feminino , Humanos , Masculino , Casamento , Modelos Genéticos , Taxa de Mutação
6.
Emerg Top Life Sci ; 4(2): 111-118, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32830859

RESUMO

The patterns of the large-scale spatial organization of chromatin in interphase human somatic cells are not random. Such patterns include the radial separation of euchromatin and heterochromatin, the territorial organization of individual chromosomes, the non-random locations of chromosome territories and the differential positioning of the two X chromosomes in female cells. These features of large-scale nuclear architecture follow naturally from the hypothesis that ATP-consuming non-equilibrium processes associated with highly transcribed regions of chromosomes are a source of 'active' forces. These forces are in excess of those that arise from Brownian motion. Simulations of model chromosomes that incorporate such activity recapitulate these features. In addition, they reproduce many other aspects of the spatial organization of chromatin at large scales that are known from experiments. Our results, reviewed here, suggest that the distribution of transcriptional activity across chromosomes underlies many aspects of large-scale nuclear architecture that were hitherto believed to be unrelated.


Assuntos
Cromatina/química , Cromatina/metabolismo , Modelos Biológicos , Trifosfato de Adenosina/metabolismo , Linhagem Celular , Núcleo Celular/genética , Cromossomos Humanos X/metabolismo , Reparo do DNA , Feminino , Expressão Gênica , Humanos , Interfase/genética , Transcrição Genética
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 942-945, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820504

RESUMO

OBJECTIVE: To explore the genetic basis for a patient with premature ovarian insufficiency. METHODS: Chromosomal G-banding and C-banding, single nucleotide polymorphism array (SNP-array), fluorescence in situ hybridization (FISH) and Y chromosome microdeletion assay were used for the analysis. RESULTS: With the combined techniques, the patient was found to carry a Xq;Yq translocation, with a karyotype of 46,X,der(X)t(X;Y)(q25;q12).ish der(X)(Tel XYp+,Tel XYq+,Yq12+). CONCLUSION: Unbalanced Xq;Yq translocation probably underlay the premature ovarian insufficiency in this patient.


Assuntos
Cromossomos Humanos X/genética , Insuficiência Ovariana Primária , Translocação Genética , Bandeamento Cromossômico , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/genética
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 859-862, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761595

RESUMO

OBJECTIVE: To explore the clinical phenotype and genetic diagnosis of a patient featuring secondary amenorrhea, breast dysplasia and mental retardation. METHODS: Peripheral venous blood samples were collected from the patient and her family members and subjected to G-banding karyotyping and single nucleotide polymorphism array (SNP-array) analysis. RESULTS: The patient was found to have a karyotype of 46,X,der(X)(12qter→ 12q22::Xq23→ Xpter)mat, her mother had a karyotype of 46,X,t(X;12)(Xpter→ Xq23::12q22→ 12qter;12pter→ 12q22::Xq23→ Xqter), while her father and brother were both 46,XY. SNP-array analysis suggested the patient to be arr[hg19]12q22q24.33(94 792 972-133 777 562)× 3, Xq23q28(108 786 070-155 233 098)×1. CONCLUSION: The abnormal phenotypes of the patient can probably be attributed to the presence of Xq23-qter deletion and 12q22-qter duplication, both have derived from her mother's balanced t (X;12) translocation.


Assuntos
Deleção Cromossômica , Duplicação Cromossômica , Testes Genéticos , Translocação Genética , Bandeamento Cromossômico , Cromossomos Humanos Par 12 , Cromossomos Humanos X , Feminino , Humanos , Cariotipagem , Mães , Fenótipo
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 863-866, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761596

RESUMO

OBJECTIVE: To provide prenatal diagnosis for a pregnant women carrying a chromosome translocations using single nucleotide polymorphism array (SNP-array). METHODS: The fetus and its parents were subjected to chromosome karyotyping and SNP array analysis. RESULTS: A Xp22.12 microduplication was identified in the fetus with a size of 496.3 kb. Search of literature and database indicated the microduplication to be variant of unclear significance. The phenotypically normal mother has carried a 505.8 kb duplication at the same position. The father was normal for the testing. The couple decided to continue with the pregnancy and gave birth to a healthy girl at full-term. No abnormality was found during the follow-up. CONCLUSION: The Xp22.12 microduplication encompassed part of RPS6KA3 gene, which shows various features of Coffin-Lowry syndrome. Female with Xp22.12 microduplications may be asymptomatic carriers due to X chromosome inactivation. Our case may provide data for delineating the phenotype-genotype correlation of Xp22.12 microduplication.


Assuntos
Duplicação Cromossômica , Cromossomos Humanos X , Diagnóstico Pré-Natal , Feminino , Feto , Testes Genéticos , Humanos , Cariotipagem , Polimorfismo de Nucleotídeo Único , Gravidez
11.
Nature ; 585(7823): 79-84, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32663838

RESUMO

After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist1,2. Here we present a human genome assembly that surpasses the continuity of GRCh382, along with a gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome3, we reconstructed the centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis ampliconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes.


Assuntos
Cromossomos Humanos X/genética , Genoma Humano/genética , Telômero/genética , Centrômero/genética , Ilhas de CpG/genética , Metilação de DNA , DNA Satélite/genética , Feminino , Humanos , Mola Hidatiforme/genética , Masculino , Gravidez , Reprodutibilidade dos Testes , Testículo/metabolismo
13.
Mol Cell ; 79(5): 836-845.e7, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32649884

RESUMO

The inactive X chromosome (Xi) is inherently susceptible to genomic aberrations. Replication stress (RS) has been proposed as an underlying cause, but the mechanisms that protect from Xi instability remain unknown. Here, we show that macroH2A1.2, an RS-protective histone variant enriched on the Xi, is required for Xi integrity and female survival. Mechanistically, macroH2A1.2 counteracts its structurally distinct and equally Xi-enriched alternative splice variant, macroH2A1.1. Comparative proteomics identified a role for macroH2A1.1 in alternative end joining (alt-EJ), which accounts for Xi anaphase defects in the absence of macroH2A1.2. Genomic instability was rescued by simultaneous depletion of macroH2A1.1 or alt-EJ factors, and mice deficient for both macroH2A1 variants harbor no overt female defects. Notably, macroH2A1 splice variant imbalance affected alt-EJ capacity also in tumor cells. Together, these findings identify macroH2A1 splicing as a modulator of genome maintenance that ensures Xi integrity and may, more broadly, predict DNA repair outcome in malignant cells.


Assuntos
Processamento Alternativo , Reparo do DNA , Epigênese Genética , Instabilidade Genômica , Histonas/fisiologia , Anáfase , Animais , Linhagem Celular , Instabilidade Cromossômica , Cromossomos Humanos X , Feminino , Histonas/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
14.
Nat Rev Genet ; 21(9): 555-571, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32514155

RESUMO

Genomic imprinting and X-chromosome inactivation (XCI) are classic epigenetic phenomena that involve transcriptional silencing of one parental allele. Germline-derived differential DNA methylation is the best-studied epigenetic mark that initiates imprinting, but evidence indicates that other mechanisms exist. Recent studies have revealed that maternal trimethylation of H3 on lysine 27 (H3K27me3) mediates autosomal maternal allele-specific gene silencing and has an important role in imprinted XCI through repression of maternal Xist. Furthermore, loss of H3K27me3-mediated imprinting contributes to the developmental defects observed in cloned embryos. This novel maternal H3K27me3-mediated non-canonical imprinting mechanism further emphasizes the important role of parental chromatin in development and could provide the basis for improving the efficiency of embryo cloning.


Assuntos
Cromossomos Humanos X , Metilação de DNA , Impressão Genômica , Histonas/metabolismo , Inativação do Cromossomo X , Animais , Gametogênese/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lisina/metabolismo
15.
Cytogenet Genome Res ; 160(5): 245-254, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32485717

RESUMO

Chromosomal microdeletion syndromes present with a wide spectrum of clinical phenotypes that depend on the size and gene content of the affected region. In a healthy carrier, epigenetic mechanisms may compensate for the same microdeletion, which may segregate through several generations without any clinical symptoms until the epigenetic modifications no longer function. We report 2 novel cases of Xq24 microdeletions inherited from mothers with extremely skewed X-chromosome inactivation (sXCI). The first case is a boy presenting with X-linked mental retardation, Nascimento type, due to a 168-kb Xq24 microdeletion involving 5 genes (CXorf56, UBE2A, NKRF, SEPT6, and MIR766) inherited from a healthy mother and grandmother with sXCI. In the second family, the presence of a 239-kb Xq24 microdeletion involving 3 additional genes (SLC25A43, SLC25A5-AS1, and SLC25A5) was detected in a woman with sXCI and a history of recurrent pregnancy loss with a maternal family history without reproductive wastages or products of conception. These cases provide evidence that women with an Xq24 microdeletion and sXCI may be at risk for having a child with intellectual disability or for experiencing a pregnancy loss due to the ontogenetic pleiotropy of a chromosomal microdeletion and its incomplete penetrance modified by sXCI.


Assuntos
Aborto Habitual/genética , Deleção Cromossômica , Cromossomos Humanos X/genética , Mães , Enzimas de Conjugação de Ubiquitina/deficiência , Enzimas de Conjugação de Ubiquitina/genética , Inativação do Cromossomo X/genética , Adulto , Pré-Escolar , Epigênese Genética , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Fenótipo , Síndrome , Adulto Jovem
16.
Nat Genet ; 52(7): 680-691, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541925

RESUMO

We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.


Assuntos
Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Afro-Americanos , Cromossomos Humanos X , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etnologia , Angiopatias Diabéticas/genética , Europa (Continente) , Feminino , Estudos de Associação Genética , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Polimorfismo de Nucleotídeo Único , Medição de Risco
17.
Cell Mol Life Sci ; 77(20): 4069-4080, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32356180

RESUMO

MicroRNAs (miRNA) are small-non coding RNAs endowed with great regulatory power, thus playing key roles not only in almost all physiological pathways, but also in the pathogenesis of several diseases. Surprisingly, genomic distribution analysis revealed the highest density of miRNA sequences on the X chromosome; this evolutionary conserved mammalian feature equips females with a larger miRNA machinery than males. However, miRNAs contribution to some X-related conditions, properties or functions is still poorly explored. With the aim to support and focus research in the field, this review analyzes the literature and databases about X-linked miRNAs, trying to understand how miRNAs could contribute to emerging gender-biased functions and pathological mechanisms, such as immunity and cancer. A fine map of miRNA sequences on the X chromosome is reported, and their known functions are discussed; in addition, bioinformatics functional analyses of the whole X-linked miRNA targetome (predicted and validated) were performed. The emerging scenario points to different gaps in the knowledge that should be filled with future experimental investigations, also in terms of possible implications and pathological perspectives for X chromosome aneuploidy syndromes, such as Turner and Klinefelter syndromes.


Assuntos
Cromossomos Humanos X/genética , MicroRNAs/genética , Animais , Biologia Computacional/métodos , Humanos , Síndrome de Klinefelter/genética , Neoplasias/genética , Síndrome de Turner/genética
18.
Int J Mol Sci ; 21(10)2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32423094

RESUMO

In December 2019, a novel severe acute respiratory syndrome (SARS) from a new coronavirus (SARS-CoV-2) was recognized in the city of Wuhan, China. Rapidly, it became an epidemic in China and has now spread throughout the world reaching pandemic proportions. High mortality rates characterize SARS-CoV-2 disease (COVID-19), which mainly affects the elderly, causing unrestrained cytokines-storm and subsequent pulmonary shutdown, also suspected micro thromboembolism events. At the present time, no specific and dedicated treatments, nor approved vaccines, are available, though very promising data come from the use of anti-inflammatory, anti-malaria, and anti-coagulant drugs. In addition, it seems that males are more susceptible to SARS-CoV-2 than females, with males 65% more likely to die from the infection than females. Data from the World Health Organization (WHO) and Chinese scientists show that of all cases about 1.7% of women who contract the virus will die compared with 2.8% of men, and data from Hong Kong hospitals state that 32% of male and 15% of female COVID-19 patients required intensive care or died. On the other hand, the long-term fallout of coronavirus may be worse for women than for men due to social and psychosocial reasons. Regardless of sex- or gender-biased data obtained from WHO and those gathered from sometimes controversial scientific journals, some central points should be considered. Firstly, SARS-CoV-2 has a strong interaction with the human ACE2 receptor, which plays an essential role in cell entry together with transmembrane serine protease 2 (TMPRSS2); it is interesting to note that the ACE2 gene lays on the X-chromosome, thus allowing females to be potentially heterozygous and differently assorted compared to men who are definitely hemizygous. Secondly, the higher ACE2 expression rate in females, though controversial, might ascribe them the worst prognosis, in contrast with worldwide epidemiological data. Finally, several genes involved in inflammation are located on the X-chromosome, which also contains high number of immune-related genes responsible for innate and adaptive immune responses to infection. Other genes, out from the RAS-pathway, might directly or indirectly impact on the ACE1/ACE2 balance by influencing its main actors (e.g., ABO locus, SRY, SOX3, ADAM17). Unexpectedly, the higher levels of ACE2 or ACE1/ACE2 rebalancing might improve the outcome of COVID-19 in both sexes by reducing inflammation, thrombosis, and death. Moreover, X-heterozygous females might also activate a mosaic advantage and show more pronounced sex-related differences resulting in a sex dimorphism, further favoring them in counteracting the progression of the SARS-CoV-2 infection.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Predisposição Genética para Doença , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Betacoronavirus/fisiologia , Cromossomos Humanos X , Infecções por Coronavirus/imunologia , Feminino , Humanos , Masculino , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/imunologia , Serina Endopeptidases/genética , Fatores Sexuais
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 584-587, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335892

RESUMO

With the application of BACs-on-BeadsTM (BoBs) and array-comparative genome hybridization (aCGH) technologies in prenatal diagnosis, microdeletion/microduplications at Xp22.3 have been frequently detected. However, the relatively high prevalence and lack of knowledge of such disorders have brought difficulties for clinical genetic counseling. Here, recent progress of research on microdeletion/microduplications at Xp22.3, including epidemiology, pathogenesis, clinical manifestation, and prenatal diagnosis, is reviewed.


Assuntos
Cromossomos Humanos X , Diagnóstico Pré-Natal , Cromossomos Humanos X/genética , Hibridização Genômica Comparativa , Feminino , Aconselhamento Genético , Humanos , Cariotipagem , Gravidez , Pesquisa/tendências
20.
G Ital Nefrol ; 37(2)2020 Apr 09.
Artigo em Italiano | MEDLINE | ID: mdl-32281760

RESUMO

Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disorder, mostly caused by antidiuretic hormone receptor type 2 (ADHR2) gene mutations, which are inherited as X-linked traits. Less than 10% of cases are due to mutations in the aquaporin-2 (AQP2) gene, inherited in autosomal recessive or dominant manner. We report the case of two adult sisters, of 30 and 27 years of age, diagnosed in early infancy with X-linked CNDI. The patients' sex and family history did not fit in well with this diagnosis, so we sequenced the coding regions of the ADHR2 and AQP2 genes. As expected, no mutations were found in the ADHR2 gene, while we found a compound heterozygosis for two different mutations in the AQP2 gene. A missense mutation (c. 439G>A, p.Ala147Thr), an already known cause of CNDI, and a novel missense putative mutation of an adenine to cytosine at position 551 (c.551A>C), resulting in the substitution of asparagine with threonine at amino acid position 184 (p.Asn184Thr). This second mutation changes a fundamental extracellular Asn-Pro-Ala motif (NPA) of the AQP2 protein, inhibiting its function. Its pathogenicity has been confirmed by in silico predictions and is in line with comparable alterations to the intracellular NPA motif of the AQP2 protein.


Assuntos
Cromossomos Humanos X/genética , Diabetes Insípido Nefrogênico/genética , Receptores de Vasopressinas/genética , Adulto , Aquaporina 2 , Análise Mutacional de DNA , Feminino , Humanos , Mutação de Sentido Incorreto , Linhagem
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