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1.
Nat Commun ; 12(1): 892, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563972

RESUMO

Given their copy number differences and unique modes of inheritance, the evolved gene content and expression of sex chromosomes is unusual. In many organisms the X and Y chromosomes are inactivated in spermatocytes, possibly as a defense mechanism against insertions into unpaired chromatin. In addition to current sex chromosomes, Drosophila has a small gene-poor X-chromosome relic (4th) that re-acquired autosomal status. Here we use single cell RNA-Seq on fly larvae to demonstrate that the single X and pair of 4th chromosomes are specifically inactivated in primary spermatocytes, based on measuring all genes or a set of broadly expressed genes in testis we identified. In contrast, genes on the single Y chromosome become maximally active in primary spermatocytes. Reduced X transcript levels are due to failed activation of RNA-Polymerase-II by phosphorylation of Serine 2 and 5.


Assuntos
Drosophila/genética , Cromossomos Sexuais/genética , Espermatócitos/metabolismo , Animais , Drosophila/crescimento & desenvolvimento , Regulação da Expressão Gênica , Genes Ligados ao Cromossomo X/genética , Genes Ligados ao Cromossomo Y/genética , Larva/genética , Larva/crescimento & desenvolvimento , Masculino , Especificidade de Órgãos , RNA Polimerase II/metabolismo , Cromossomos Sexuais/metabolismo , Espermatogênese/genética , Testículo/citologia , Testículo/metabolismo , Transcrição Genética
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.
Am J Hum Genet ; 108(2): 309-323, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33472045

RESUMO

Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent progress has identified several MMAF-associated genes with an autosomal recessive inheritance in human affected individuals, but the etiology in approximately 40% of affected individuals remains unknown. Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF. These three CFAP47 variants were absent in human control population genome databases and were predicted to be deleterious by multiple bioinformatic tools. CFAP47 encodes a cilia- and flagella-associated protein that is highly expressed in testis. Immunoblotting and immunofluorescence assays revealed obviously reduced levels of CFAP47 in spermatozoa from all three men harboring deleterious missense variants of CFAP47. Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene. All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes. We also generated a Cfap47-mutated mouse model, the adult males of which were sterile and presented with reduced sperm motility and abnormal flagellar morphology and movement. However, fertility could be rescued by the use of intra-cytoplasmic sperm injections (ICSIs). Altogether, our experimental observations in humans and mice demonstrate that hemizygous mutations in CFAP47 can induce X-linked MMAF and asthenoteratozoospermia, for which good ICSI prognosis is suggested. These findings will provide important guidance for genetic counseling and assisted reproduction treatments.


Assuntos
Astenozoospermia/genética , Infertilidade Masculina/genética , Animais , Astenozoospermia/patologia , Astenozoospermia/fisiopatologia , Estudos de Coortes , Feminino , Deleção de Genes , Genes Ligados ao Cromossomo X , Hemizigoto , Humanos , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Mutação , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Injeções de Esperma Intracitoplásmicas , Motilidade Espermática , Cauda do Espermatozoide/ultraestrutura , Espermatozoides/patologia , Espermatozoides/fisiologia , Espermatozoides/ultraestrutura , Sequenciamento Completo do Exoma
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 823-827, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761587

RESUMO

OBJECTIVE: To explore the genetic basis for a child featuring X-linked intellectual disability. METHODS: The 1-year-and-6-month-old child presented with growth retardation, intellectual disability and bilateral alternating squint. With DNA extracted from the child and his parents' peripheral venous blood samples, whole exome sequencing was carried out to identify potential variants that can explain his condition. Suspected variants were validated by Sanger sequencing. The impact of variants was predicted by bioinformatic tools. RESULTS: The child was found to harbor a de novo nonsense c.3163C>T (p.Arg1055*) variant of the IQSEC2 gene. The variant, unreported previously, was predicted to be pathogenic based on MutationTaster, PROVEAN and SIFT. Analysis using a HomoloGene system suggested Arg1055 in IQSEC2 residues to be highly conserved evolutionarily, and that replacement of Arg1055 may cause destroy of the PH domain (AA 951-1085) and serious damage to the function of IQSEC2 protein. Analysis with UCSF chimera software suggested that the c.3163C>T (p.Arg1055*) variant can induce serious damages to the secondary structures of IQSEC2 protein, causing loss of its function. CONCLUSION: The patient's condition may be attributed to the de novo nonsense variant c.3163C>T (p.Arg1055*) of the IQSEC2 gene.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Códon sem Sentido , Genes Ligados ao Cromossomo X , Humanos , Lactente , Masculino , Sequenciamento Completo do Exoma
5.
J Genet ; 992020.
Artigo em Inglês | MEDLINE | ID: mdl-32529990

RESUMO

IQSEC2 is an X-linked gene highly expressed at the excitatory synapses where it plays a crucial role in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking and synaptic plasticity. To date, several males and females with severe to profound intellectual disability have been reported harbouring frameshift and nonsense variants in this gene, whereas a milder phenotype has been recognized in females carrying missense pathogenic variants. Here, we report two novel IQSEC2 variants in four females with psychiatric features and otherwise variable cognitive impairment. A female (case 1) with severe verbal language learning disorder and a psychotic episode (precipitated by exposure to anti-contraceptive pill) harboured a de novo pathogenic frameshift variant (c.1170dupG,p.Gln391Alafs*5), whereas the female proband of family 2, displaying severe psychomotor regression and complex psychiatric features carried a missense variant of uncertain significance (c.770G[A,p.Ser257Asn) that was maternally inherited. Skewed X-inactivation was noted in the carrier mother. The maternal aunt, affected by schizophrenia, was found to bear the same IQSEC2 variant. We discuss the variable clinical presentation of IQSEC2 spectrum disorders and the challenging genotype-phenotype correlation, including the possible role of environmental factors as triggers for decompensation. Our report highlights how psychiatric features may be the main clinical presentation in subtle IQSEC2 phenotype, suggesting that the prevalence of IQSEC2 mutations in patients with psychiatric disorders may be underestimated.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Mutação/genética , Feminino , Genes Ligados ao Cromossomo X , Estudos de Associação Genética , Humanos , Sequenciamento Completo do Exoma , Inativação do Cromossomo X
7.
Nat Commun ; 11(1): 1270, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152280

RESUMO

Prolonged cell survival occurs through the expression of specific protein isoforms generated by alternate splicing of mRNA precursors in cancer cells. How alternate splicing regulates tumor development and resistance to targeted therapies in cancer remain poorly understood. Here we show that RNF113A, whose loss-of-function causes the X-linked trichothiodystrophy, is overexpressed in lung cancer and protects from Cisplatin-dependent cell death. RNF113A is a RNA-binding protein which regulates the splicing of multiple candidates involved in cell survival. RNF113A deficiency triggers cell death upon DNA damage through multiple mechanisms, including apoptosis via the destabilization of the prosurvival protein MCL-1, ferroptosis due to enhanced SAT1 expression, and increased production of ROS due to altered Noxa1 expression. RNF113A deficiency circumvents the resistance to Cisplatin and to BCL-2 inhibitors through the destabilization of MCL-1, which thus defines spliceosome inhibitors as a therapeutic approach to treat tumors showing acquired resistance to specific drugs due to MCL-1 stabilization.


Assuntos
Proteínas de Ligação a DNA/genética , Genes Ligados ao Cromossomo X , Spliceossomos/metabolismo , Síndromes de Tricotiodistrofia/genética , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Processamento Alternativo/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/genética , Cisplatino/farmacologia , Citoproteção/efeitos dos fármacos , Dano ao DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Íntrons/genética , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas de Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Subunidades Proteicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(3): 252-257, 2020 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-32128740

RESUMO

Albinism is an autosomal or X-linked recessive Mendelian trait in man, which mainly manifests as hypopigmentation and related lesions of eye, skin and hair. At least 18 genes have so far been identified as causative genes for albinism. The mutational spectrum is population-specific. Molecular genotyping of albinism is important for genetic and prenatal diagnosis, and is a prerequisite for the practice of precision medicine. Based on long-term study of albinism in Chinese population, a guideline for the clinical management of albinism is provided.


Assuntos
Albinismo/diagnóstico , Albinismo/terapia , Guias de Prática Clínica como Assunto , Grupo com Ancestrais do Continente Asiático , China , Genes Ligados ao Cromossomo X , Humanos , Mutação
9.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165730, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32070770

RESUMO

Widespread random monoallelic gene expression (RMAE) effects influence about 10% of human genes. However, the mechanisms by which RME of autosomal genes is established and those by which it is maintained both remain open questions. Because the choice of allelic expression is randomly performed cell-by-cell, the RMAE mechanism is not observable in non-clonal cell populations or in whole tissues. Several target genes of MeCP2, the gene involved in Rett syndrome (RTT), have been previously described as subject to RMAE, suggesting that MeCP2 may be involved in the establishment and/or maintenance of RME of autosomal genes. To improve our knowledge on this largely unknown phenomenon, and to study the role of MeCP2 in RMAE, we compared RMA gene expression profiles in clonal cell cultures expressing wild-type MeCP2 versus mutant MeCP2 from a RTT patient carrying a pathogenic non-sense variant. Our data clearly demonstrated that MeCP2 deficiency does not affect significantly allelic gene expression of X-linked genes, imprinted genes as well as the RMAE profile in the majority of genes. However, the functional deficiency in MeCP2 appeared to disrupt the mono-allelic or the bi-allelic expression of at least 49 genes allowing us to define a specific signature of MECP2 mutated clones.


Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Alelos , Desequilíbrio Alélico/genética , Regulação da Expressão Gênica/genética , Genes Ligados ao Cromossomo X/genética , Humanos , Mutação/genética , Fenótipo , Síndrome de Rett/patologia
10.
BMC Med Genet ; 21(1): 38, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32085749

RESUMO

BACKGROUND: Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases. METHODS: We performed whole exome sequencing (WES) of two maternal adult half-brothers with syndromic PBS (PBS + Otopalatodigital spectrum disorder [OPDSD]) and two unrelated sporadic individuals with isolated PBS and further functionally validated the identified mutations. RESULTS: We identified three unreported hemizygous missense point mutations in the X-chromosome gene Filamin A (FLNA) (c.4952 C > T (p.A1448V), c.6727C > T (p.C2160R), c.5966 G > A (p.G2236E)) in two related cases and two unrelated sporadic individuals. Two of the three PBS mutations map to the highly regulatory, stretch-sensing Ig19-21 region of FLNA and enhance binding to intracellular tails of the transmembrane receptor ß-integrin 1 (ITGß1). CONCLUSIONS: FLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold, transmitting force signals from the actin-myosin motor units and cytoskeleton via binding partners to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in multiple unrelated individuals and expands the phenotypic spectrum associated with FLNA in males surviving even into adulthood.


Assuntos
Filaminas/genética , Genes Ligados ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Síndrome do Abdome em Ameixa Seca/genética , Adulto , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Predisposição Genética para Doença , Genótipo , Hemizigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Síndrome do Abdome em Ameixa Seca/fisiopatologia , Sequenciamento Completo do Exoma
11.
Int J Mol Sci ; 21(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32070051

RESUMO

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) was first described by Dr. Charles Hunter in 1917. Since then, about one hundred years have passed and Hunter syndrome, although at first neglected for a few decades and afterwards mistaken for a long time for the similar disorder Hurler syndrome, has been clearly distinguished as a specific disease since 1978, when the distinct genetic causes of the two disorders were finally identified. MPS II is a rare genetic disorder, recently described as presenting an incidence rate ranging from 0.38 to 1.09 per 100,000 live male births, and it is the only X-linked-inherited mucopolysaccharidosis. The complex disease is due to a deficit of the lysosomal hydrolase iduronate 2-sulphatase, which is a crucial enzyme in the stepwise degradation of heparan and dermatan sulphate. This contributes to a heavy clinical phenotype involving most organ-systems, including the brain, in at least two-thirds of cases. In this review, we will summarize the history of the disease during this century through clinical and laboratory evaluations that allowed its definition, its correct diagnosis, a partial comprehension of its pathogenesis, and the proposition of therapeutic protocols. We will also highlight the main open issues related to the possible inclusion of MPS II in newborn screenings, the comprehension of brain pathogenesis, and treatment of the neurological compartment.


Assuntos
Genes Ligados ao Cromossomo X/genética , Iduronato Sulfatase/genética , Mucopolissacaridose II/genética , Mucopolissacaridose II/terapia , Encéfalo/patologia , Humanos , Masculino , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/patologia , Fenótipo
12.
Nat Commun ; 11(1): 352, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953404

RESUMO

CRISPR-based gene drives can spread through wild populations by biasing their own transmission above the 50% value predicted by Mendelian inheritance. These technologies offer population-engineering solutions for combating vector-borne diseases, managing crop pests, and supporting ecosystem conservation efforts. Current technologies raise safety concerns for unintended gene propagation. Herein, we address such concerns by splitting the drive components, Cas9 and gRNAs, into separate alleles to form a trans-complementing split-gene-drive (tGD) and demonstrate its ability to promote super-Mendelian inheritance of the separate transgenes. This dual-component configuration allows for combinatorial transgene optimization and increases safety by restricting escape concerns to experimentation windows. We employ the tGD and a small-molecule-controlled version to investigate the biology of component inheritance and resistant allele formation, and to study the effects of maternal inheritance and impaired homology on efficiency. Lastly, mathematical modeling of tGD spread within populations reveals potential advantages for improving current gene-drive technologies for field population modification.


Assuntos
Tecnologia de Impulso Genético/métodos , Genética Populacional/métodos , Alelos , Animais , Animais Geneticamente Modificados , Sequência de Bases , Sistemas CRISPR-Cas , Dípteros , Ecossistema , Feminino , Edição de Genes , Genes Ligados ao Cromossomo X , Masculino , Modelos Teóricos , RNA Guia/genética , Transgenes
13.
Genes (Basel) ; 11(1)2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31906484

RESUMO

X-linked intellectual disability (XLID) is known to contribute up to 10% of intellectual disability (ID) in males and could explain the increased ratio of affected males observed in patients with ID. Over the past decade, next-generation sequencing has clearly stimulated the gene discovery process and has become part of the diagnostic procedure. We have performed targeted next-generation sequencing of 82 XLID genes on 61 non-related male patients with suggestive non-syndromic XLID. These patients were initially referred to the molecular genetics laboratory to exclude Fragile X Syndrome. The cohort includes 47 male patients with suggestive X-linked family history of ID meaning that they had half-brothers or maternal cousins or uncles affected; and 14 male patients with ID and affected brothers whose mothers show skewed X-inactivation. Sequencing data analysis identified 17 candidate variants in 16 patients. Seven families could be re-contacted and variant segregation analysis of the respective eight candidate variants was performed: HUWE1, IQSEC2, MAOA, MED12, PHF8, SLC6A8, SLC9A6, and SYN1. Our results show the utility of targeted next-generation sequencing in unravelling the genetic origin of XLID, especially in retrospective cases. Variant segregation and additional studies like RNA sequencing and biochemical assays also helped in re-evaluating and further classifying the genetic variants found.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Retardo Mental Ligado ao Cromossomo X/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Exoma/genética , Síndrome do Cromossomo X Frágil , Genes Ligados ao Cromossomo X/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Complexo Mediador/genética , Monoaminoxidase/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Linhagem , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Estudos Retrospectivos , Trocadores de Sódio-Hidrogênio/genética , Fatores de Transcrição , Sequenciamento Completo do Exoma/métodos
14.
Eur J Med Genet ; 63(3): 103768, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31536828

RESUMO

Mutations in MED12 gene have been described in association with syndromic and non-syndromic X-linked intellectual disability (XLID). Up to date at least three distinct XLID syndromes have been described: FG syndrome, Lujan-Fryns syndrome (LS) and Ohdo syndrome (OSMKB). In the last years, thanks to the massive use of next generation sequencing techniques (NGS) it has been possible to discover at least 16 others MED12 mutations and to expand the phenotype of MED12-related disorders. Here we report three subjects from a large non-consanguineous family presenting with a mild to severe ID, important speech delay, behavior problems, dysmorphic facial features and hearing loss. NGS allows us to detect the MED12 missense variant c.3883C > T (p.(Arg1295Cys)) carried by the three patients. This variant has been reported in 2016 by Hu et al. in one family from a big cohort of XLID families. This clinical report contributes to expanding the phenotype associated with MED12-mutations.


Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/genética , Anus Imperfurado/genética , Blefarofimose/genética , Blefaroptose/genética , Constipação Intestinal/genética , Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Síndrome de Marfan/genética , Complexo Mediador/genética , Retardo Mental Ligado ao Cromossomo X/genética , Hipotonia Muscular/congênito , Anormalidades Múltiplas/fisiopatologia , Adolescente , Agenesia do Corpo Caloso/fisiopatologia , Anus Imperfurado/fisiopatologia , Blefarofimose/fisiopatologia , Blefaroptose/fisiopatologia , Criança , Constipação Intestinal/fisiopatologia , Anormalidades Craniofaciais/fisiopatologia , Genes Ligados ao Cromossomo X , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Cardiopatias Congênitas/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Síndrome de Marfan/fisiopatologia , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Pessoa de Meia-Idade , Hipotonia Muscular/genética , Hipotonia Muscular/fisiopatologia , Mutação de Sentido Incorreto , Linhagem
15.
Eur J Med Genet ; 63(3): 103737, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31419599

RESUMO

Mutations in KDM5C (lysine (K)-specific demethylase 5C) were causally associated with up to 3% of X-linked intellectual disability (ID) in males. By exome and Sanger sequencing, a novel frameshift KDM5C variant, predicted to eliminate the JmjC catalytic domain from the protein, was identified in two monozygotic twins and their older brother, which was inherited from their clinically normal mother, who had completely skewed X-inactivation. DNA methylation (DNAm) data were evaluated using the Illumina 450 K Methylation Beadchip arrays. Comparison of methylation levels between the three patients and male controls identified 399 differentially methylated CpG sites, which were enriched among those CpG sites modulated during brain development. Most of them were hypomethylated (72%), and located mainly in shores, whereas the hypermethylated CpGs were more represented in open sea regions. The DNAm changes did not differ between the monozygotic twins nor between them and their older sibling, all presenting a global hypomethylation, similar to other studies that associated DNA methylation changes to different KDM5C mutations. The 38 differentially methylated regions (DMRs) were enriched for H3K4me3 marks identified in developing brains. The remarkable similarity between the methylation changes in the monozygotic twins and their older brother is indicative that these epigenetic changes were mostly driven by the KDM5C mutation.


Assuntos
Encéfalo/metabolismo , Doenças em Gêmeos/genética , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Gêmeos Monozigóticos/genética , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Criança , Ilhas de CpG , Metilação de DNA , Doenças em Gêmeos/fisiopatologia , Epigênese Genética , Mutação da Fase de Leitura , Genes Ligados ao Cromossomo X/genética , Histonas/genética , Histonas/metabolismo , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Análise em Microsséries , Irmãos , Sequenciamento Completo do Exoma
16.
Eur J Med Genet ; 63(2): 103658, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31048080

RESUMO

BACKGROUND: Pathogenic variants in the BCOR gene have been identified in males with X-linked recessive microphthalmia and in females with X-linked dominant oculofaciocardiodental (OFCD) syndrome. This latter condition has previously been regarded as rare but the increased availability of genetic testing in recent years has led to the identification of a greater number of patients. METHODS: We report the clinical and molecular findings in a series of 10 patients with pathogenic BCOR variants from 5 families, all seen in a single institution over a two year period. RESULTS: We emphasize the phenotypic variability in this cohort and the diverse genetic mechanisms involved which included point mutations and deletions of BCOR as well as the occurrence of gonadal and somatic mosaicism. CONCLUSION: In this report we demonstrate the novel findings of four newly identified variants in BCOR associated with an OFCD phenotype, and suggest that the frequency of this condition in females presenting with congenital cataract, including unilateral cataract, is more common than anticipated. We demonstrate the utility of screening for genetic causes of congenital cataract. Although gonadal mosaicism in OFCD had previously been reported, we demonstrate the presence of somatic mosaicism where BCOR mutations may only be detected in DNA from tissues other than blood such as buccal cells.


Assuntos
Catarata/congênito , Catarata/diagnóstico , Catarata/genética , Defeitos dos Septos Cardíacos/diagnóstico , Defeitos dos Septos Cardíacos/genética , Microftalmia/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Genes Ligados ao Cromossomo X , Humanos , Lactente , Recém-Nascido , Microftalmia/diagnóstico , Mosaicismo , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo , Mutação Puntual , Doenças Raras/genética , Análise de Sequência de DNA , Deleção de Sequência
18.
Clin Genet ; 97(3): 418-425, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31705537

RESUMO

To better understand the landscape of female phenotypic expression in X-linked intellectual disability (XLID), we surveyed the literature for female carriers of XLID gene alterations (n = 1098) and combined this with experience evaluating XLID kindreds at the Greenwood Genetic Center (n = 341) and at the University of Adelaide (n = 157). One-hundred forty-four XLID genes were grouped into nine categories based on the level of female phenotypic expression, ranging from no expression to female only expression. For each gene, the clinical presentation, gene expression in blood, X-inactivation (XI) pattern, biological pathway involved, and whether the gene escapes XI were noted. Among the XLID conditions, 88 (61.1%) exhibited female cognitive phenotypic expression only, while 56 (38.9%) had no female phenotypic expression (n = 45), phenotype expression with normal cognition in females (n = 8), or unknown status for female phenotypic expression (n = 3). In twenty-four (16.6%) XLID genes, XI was consistently skewed in female carriers, in 54 (37.5%) XI showed variable skewing, and in 33 (22.9%) XI was consistently random. The XI pattern was unknown in 33 (22.9%) XLID conditions. Therefore, there is evidence of a female carrier phenotype in the majority of XLID conditions although how exactly XI patterns influence the female phenotype in XLID conditions remains unclear.


Assuntos
Deficiência Intelectual/genética , Feminino , Genes Ligados ao Cromossomo X/genética , Heterozigoto , Humanos , Fenótipo , Inativação do Cromossomo X
20.
Genet Test Mol Biomarkers ; 24(1): 54-58, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31829726

RESUMO

Aim: Lennox-Gastaut syndrome (LGS) is a severe type of childhood-onset epilepsy with multiple types of seizures, specific discharges on electroencephalography, and intellectual disability. However, LGS-related genes are largely unknown. To identify causative genes related to LGS, we collected and analyzed data from a three-generation Korean family in which one member had LGS and two had intellectual disability. Methods: Genomic DNAs were extracted from blood samples of all participants and used in whole-exome sequencing (WES). Genetic variants were detected by the Genome Analysis Toolkit and confirmed by Sanger sequencing. Variant pathogenicity was evaluated by prediction programs and the American College of Medical Genetics criteria. The LGS patient had generalized slow spike-and-wave discharges, multiple types of seizures, and developmental delay. Results: Analyses of the WES data from the family revealed a novel variant (c.1048G>A, p.Ala350Thr) in the IQ motif and Sec7 domain 2 (IQSEC2). This variant is within a highly evolutionarily conserved IQ-like motif, indicating a decrease in the calmodulin-binding capacity or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid transmission. The hemizygous variant in the male with LGS was a maternally inherited X-linked variant from the heterozygous maternal grandmother and mother, both of whom had intellectual disability. Conclusion: These findings indicate that the variant of IQSEC2 triggered both LGS and intellectual disability dependent on sex in this family. We report a novel X-linked inherited IQSEC2 variant for LGS and intellectual disability, which enhances the spectrum of variants in the IQ-like motif of IQSEC2.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Síndrome de Lennox Gastaut/genética , Adulto , Criança , Epilepsia/genética , Família , Feminino , Genes Ligados ao Cromossomo X/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Masculino , Linhagem , República da Coreia , Sequenciamento Completo do Exoma
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