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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 853-856, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487529

RESUMO

OBJECTIVE: To analyze the prenatal ultrasonic characteristics and genetic features of 14 fetuses with chromosome 22q11 microdeletion syndrome (22q11DS). METHODS: 4989 fetuses were analyzed by using single nucleotide polymorphism array (SNP array) in the Fujian Maternal and Child Health Hospital from November 2016 to November 2019. RESULTS: SNP array showed that 11 fetuses had classic 3 Mb microdeletion in 22q11 region, one fetus had 2.0 Mb microdeletion, and two fetuses had 1.0 Mb microdeletion. The 1.0 Mb microdeletion in 22q11 region contains SNAP29 and CRKL genes, which may increase the risk of congenital renal malformation and cardiovascular malformation. CONCLUSION: Prenatal ultrasonic characteristics of fetuses with 22q11 microdeletion syndrome vary, and SNP array is a powerful tool to diagnose such diseases, which can provide accurate genetic diagnosis and enable prenatal diagnosis.


Assuntos
Síndrome da Deleção 22q11/diagnóstico por imagem , Diagnóstico Pré-Natal , Ultrassom , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Feminino , Feto , Testes Genéticos , Humanos , Gravidez
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 917-920, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487544

RESUMO

Phelan-McDermid syndrome (PMS)(OMIM#606232) is a rare genetic disorder caused by a deletion of the distal long arm of chromosome 22q13 involving a variety of clinical features with considerably heterogeneous degrees of severity. This syndrome is characterized by global developmental delay, intellectual disability, hypotonia, absent or severely delayed speech, minor dysmorphic features and autism spectrum disorder. PMS is easy to be misdiagnosed due to the lack of specific clinical manifestations. SHANK3 has been identified as the critical candidate gene for the neurological features of this syndrome. However, some studies have shown that other genes located in the 22q13 region may have a role in the formation of symptoms in individuals with PMS. This article provides a review for recent progress made in research on PMS including etiology, clinical manifestation, diagnosis, and treatment, with a particular emphasis on clinical diagnosis and treatment.


Assuntos
Transtorno do Espectro Autista , Transtornos Cromossômicos , Transtorno do Espectro Autista/genética , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22 , Humanos , Proteínas do Tecido Nervoso/genética
3.
Nat Commun ; 12(1): 4922, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389729

RESUMO

CRISPR-Cas9 is a promising technology for gene therapy. However, the ON-target genotoxicity of CRISPR-Cas9 nuclease due to DNA double-strand breaks has received little attention and is probably underestimated. Here we report that genome editing targeting globin genes induces megabase-scale losses of heterozygosity (LOH) from the globin CRISPR-Cas9 cut-site to the telomere (5.2 Mb). In established lines, CRISPR-Cas9 nuclease induces frequent terminal chromosome 11p truncations and rare copy-neutral LOH. In primary hematopoietic progenitor/stem cells, we detect 1.1% of clones (7/648) with acquired megabase LOH induced by CRISPR-Cas9. In-depth analysis by SNP-array reveals the presence of copy-neutral LOH. This leads to 11p15.5 partial uniparental disomy, comprising two Chr11p15.5 imprinting centers (H19/IGF2:IG-DMR/IC1 and KCNQ1OT1:TSS-DMR/IC2) and impacting H19 and IGF2 expression. While this genotoxicity is a safety concern for CRISPR clinical trials, it is also an opportunity to model copy-neutral-LOH for genetic diseases and cancers.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Globinas/genética , Células-Tronco Hematopoéticas/metabolismo , Perda de Heterozigosidade/genética , Deleção de Sequência , Células Cultivadas , Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Metilação de DNA , Expressão Gênica , Células HEK293 , Células-Tronco Hematopoéticas/citologia , Humanos , Fator de Crescimento Insulin-Like II/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 768-770, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365621

RESUMO

OBJECTIVE: To carry out genetic testing for a pregnant woman with mild mental retardation, facial dysmorphism, and a history of adverse pregnancies and provide prenatal diagnosis for her. METHODS: Routine G-banded karyotyping and single nucleotide polymorphism microarray (SNP-array) analysis were performed on the couple and amniotic fluid sample. RESULTS: No karyotypic abnormality was found with the couple and amniotic fluid sample. SNP-array analysis showed that the woman has carried a 7.801 Mb microdeletion in 10q22.3q23.2, which involved 18 OMIM genes including CDHR1, BMPR1A, NRG3, GRID1 and LDB3, which are associated with facial abnormalities, developmental retardation, mental retardation and autism. The fetus also carried a 7.819 Mb deletion in the same region, while the father showed no abnormality. CONCLUSION: Both the pregnant woman and her fetus have carried a 10q22.3q23.2 microdeletion, which has provided guidance for her subsequent pregnancy.


Assuntos
Testes Genéticos , Diagnóstico Pré-Natal , Caderinas , Bandeamento Cromossômico , Deleção Cromossômica , Feminino , Feto , Humanos , Cariotipagem , Proteínas do Tecido Nervoso , Gravidez
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 779-782, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365624

RESUMO

OBJECTIVE: To explore the genetic basis for a child with febrile seizures. METHODS: Peripheral venous blood samples were taken from the child and his parents for the analysis of chromosomal karyotype and dynamic variant of the FMR1 gene. The family trio was also subjected to target capture and next generation sequencing (NGS) with a gene panel related to developmental retardation, mental retardation, language retardation, epilepsy and special facial features. RESULTS: The child was found to have a normal karyotype by conventional cytogenetic analysis (400 bands). No abnormal expansion was found with the CGG repeats of the FMR1 gene. NGS revealed that the child has carried a heterozygous c.864+1 delG variant of the MEF2C gene, which may lead to abnormal splicing and affect its protein function. The same variant was found in neither parent, suggesting that it has a de novo origin. Based on the American College of Medical Genetics and Genomics standards and guidelines, c.864+1delG variant of MEF2C gene was predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION: MEF2C, as the key gene for chromosome 5q14.3 deletion syndrome which was speculated as a cause for febrile seizures, has an autosomal dominant effect. The c.864+1delG variant of the MEF2C gene may account for the febrile seizures in this patient.


Assuntos
Transtornos Cromossômicos , Epilepsia , Deficiência Intelectual , Criança , Deleção Cromossômica , Proteína do X Frágil de Retardo Mental , Humanos , Deficiência Intelectual/genética , Cariotipagem , Fatores de Transcrição MEF2/genética
6.
Rev Med Liege ; 76(7-8): 625-628, 2021 Jul.
Artigo em Francês | MEDLINE | ID: mdl-34357716

RESUMO

KBG syndrome, named after the initials of the first 3 families reported, is a rare genetic syndrome caused by a deletion or a mutation of ANKRD11 (ankyrin repeat domain-containing protein 11) gene. Its prevalence is probably underestimated because of a variable expressivity; moreover, most of its clinical characteristics are not specific. There is no consensus about its diagnostic criteria. Ophthalmologic manifestations have sometimes been described among more frequent clinical signs. Early detection is critical and multidisciplinary care is requested in order to ensure the patient's independence. We report the case of a 16 years old boy diagnosed with a KBG syndrome after more than one year of genetic research, motivated by a short stature, high refractive errors and bilateral corneal clouding.


Assuntos
Deleção Cromossômica , Proteínas Repressoras , Anormalidades Múltiplas , Adolescente , Doenças do Desenvolvimento Ósseo , Facies , Humanos , Deficiência Intelectual , Masculino , Fenótipo , Proteínas Repressoras/genética , Anormalidades Dentárias
7.
Cytogenet Genome Res ; 161(3-4): 153-159, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34229322

RESUMO

Terminal deletions in the long arm of chromosome 4 are an uncommon event, with a worldwide incidence of approximately 0.001%. The majority of these deletions occur de novo. Terminal deletion cases are usually accompanied by clinical findings that include facial and cardiac anomalies, as well as intellectual disability. In this study, we describe the case of a 2-year-old girl, the fourth child born to consanguineous parents. While her karyotype was normal, a homozygous deletion was identified in the chromosome 4q35.2 region by subtelomeric FISH. A heterozygous deletion of the chromosome 4q35.2 region was observed in both parents. According to the literature, this is the first report of a case that has inherited a homozygous deletion of chromosome 4qter from carrier parents. Subsequent array-CGH analyses were performed on both the case and her parents. Whole-exome sequencing was also carried out to determine potential variants. We detected a NM_001111125.3:c.2329G>T (p.Glu777Ter) nonsense variant of the IQSEC2 gene in the girl, a variant that is related to X-linked intellectual disability.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 4/genética , Códon sem Sentido , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Pré-Escolar , Consanguinidade , Feminino , Genes Ligados ao Cromossomo X/genética , Homozigoto , Humanos , Cariotipagem , Telômero/genética , Sequenciamento Completo do Exoma
8.
Clin Immunol ; 229: 108801, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34280577

RESUMO

Major histocompatibility class I deficiency, due to genetic lesions in TAP1, TAP2, TAPBP, or B2M, manifests with recurrent sinopulmonary infections and granulomatous skin ulceration, and is predominately treated with antimicrobial prophylaxis and chest physiotherapy. One previous report of hematopoietic stem cell transplantation has been described in the literature, demonstrating cure of the immune defect without significant graft-versus-host disease. In this report, we expand the literature on HSCT in MHC-I deficiency with follow-up of the original patient, demonstrating maintained resolution of normal immune function and regression of the granulomatous rash 15 years post-transplant, and describe a further patient with mycobacterial disease whose transplant course was complicated by severe graft-versus-host disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe I/genética , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/terapia , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/deficiência , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/deficiência , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Criança , Deleção Cromossômica , Evolução Fatal , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Mutação com Perda de Função , Pneumonia/imunologia , Pneumonia/terapia , Doenças da Imunodeficiência Primária/imunologia , Complexo de Endopeptidases do Proteassoma/deficiência , Complexo de Endopeptidases do Proteassoma/genética , Linfócitos T/imunologia , Adulto Jovem
9.
J Neurodev Disord ; 13(1): 26, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34246244

RESUMO

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The condition is characterised by global developmental delay, ID, speech impairments, hypotonia and autistic behaviours, although its presentation and symptom severity vary widely. In this study, we provide a thorough description of the behavioural profile in PMS and explore differences related to deletion size and language ability. METHODS: We used standard clinical assessment instruments to measure altered behaviour, adaptive skills and autistic symptomatology in sixty participants with PMS (30 females, median age 8.5 years, SD=7.1). We recorded background information and other clinical manifestations and explored associations with deletion size. We performed descriptive and inferential analyses for group comparison. RESULTS: We found delayed gross and fine motor development, delayed and impaired language (~70% of participants non or minimally verbal), ID of different degrees and adaptive functioning ranging from severe to borderline impairment. Approximately 40% of participants experienced developmental regression, and half of those regained skills. Autistic symptoms were frequent and variable in severity, with a median ADOS-2 CSS score of 6 for every domain. Sensory processing anomalies, hyperactivity, attentional problems and medical comorbidities were commonplace. The degree of language and motor development appeared to be associated with deletion size. CONCLUSIONS: This study adds to previous research on the clinical descriptions of PMS and supports results suggesting wide variability of symptom severity and its association with deletion size. It makes the case for suitable psychotherapeutic and pharmacological approaches, for longitudinal studies to strengthen our understanding of possible clinical courses and for more precise genomic analysis.


Assuntos
Transtorno do Espectro Autista , Transtornos Cromossômicos , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Criança , Deleção Cromossômica , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22 , Feminino , Humanos , Fenótipo
10.
Eur J Med Genet ; 64(9): 104287, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34252586

RESUMO

BACKGROUND: The 10q26 subtelomeric microdeletion syndrome is a rare and clinically heterogeneous disorder. The precise relationships between the causative genes and the phenotype are unclear. CASE PRESENTATION: We report two new cases of 860 kb deletion of 10q26.2 identified by array CGH in a fetus with intrauterine growth retardation and his mother. The deleted region encompassed only four coding genes, DOCK1, INSYN2, NPS and FOX12. The proband had dysmorphic facies characterized by a high forehead, malformed ears, a prominent nose, and retrognathia. He had bilateral club feet, clinodactily and mild psychomotor retardation. His mother had a short stature, microcephaly, a long face with a high forehead and bitemporal narrowing, arched and sparse eyebrows, strabismus, prominent nose and chin, a thin upper lip and large protruding ears, and mild intellectual disability. CONCLUSIONS: This study presents the smallest 10q26.2 deletion so far identified, which further refines the minimal critical region associated with the 10q26 microdeletion syndrome. It focuses on three genes potentially responsible for the phenotype: DOCK1, which is the major candidate gene, and INSYN2 and NPS, which could be involved in cognitive functions.


Assuntos
Cognição , Deficiências da Aprendizagem/genética , Neuropeptídeos/genética , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 10/genética , Facies , Feminino , Humanos , Lactente , Deficiências da Aprendizagem/patologia , Masculino , Fenótipo , Proteínas rac de Ligação ao GTP/genética
11.
Eur J Med Genet ; 64(9): 104289, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34265435

RESUMO

BACKGROUND: Kleefstra syndrome type 1 (KS1, OMIM#610253) is a rare autosomal-dominant Mendelian disorder due to heterozygous mutations in the EHMT1 gene or heterozygous deletion of genomic segment of 9q34.3(9qdel). Neurodevelopmental disorder (NDD), intellectual disability (ID) and childhood-onset hypotonia are the well-known phenotypes of KS1. However, these findings were all investigated based on western patients with KS1. METHODS: KS1 patients were diagnosed by genetic tests. The clinical data was collected and the phenotypes were standardized by compared with patients that previously reported. In silico, conservational and protein structural analysis were performed to assessment the missense variants. RESULTS: Ten patients from unrelated families were diagnosed as KS1, who all had NDD and seven of them had global developmental delay (GDD) with significant personal-social disabilities. Among the ten patients, only one (1/10) patient showed neonatal or infantile obesity. The other nine patients were heterozygous variations, including three missense mutations (p.Glu235Gly, p.Asp903Gly, and p.Leu943Pro), three frameshifting mutations (p.Asn1106Lysfs*71, p.Asn1055Tyrfs*121, and p.Lys288Argfs*20), one nonsense mutation (p.Arg246*), one slice site mutation (c.3540+2T > C) and one 9q34.3 deletion in gene of EHMT1. Furthermore, missense mutations showed potential pathogenicity analyzed by in silico. CONCLUSION: We demonstrated that the clinical features in Chinese patients with KS1 were due to EHMT1 defects. We also reported seven novel variants which enriched the mutation spectrum and provided a good understanding of the pathogenesis of KS1.


Assuntos
Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/patologia , Feminino , Cardiopatias Congênitas/patologia , Heterozigoto , Histona-Lisina N-Metiltransferase/química , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Mutação , Fenótipo , Domínios Proteicos
12.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(4): 711-715, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34323054

RESUMO

Objective: To analyze the potential genetic cause of thrombocytopenia-absent radius (TAR) syndrome in a family and provide prenatal diagnosis for them. Methods: Genetic mutation analysis of the sporadic family with TAR syndrome was performed with chromosome microarray analysis (CMA), quantitative polymerase chain reaction (qPCR) and Sanger sequencing. DNA samples were collected from 4 members of the family, including the proband, her parents and her sister. CMA, qPCR and Sanger sequencing were performed to determine the pathogenic mutation and prenatal diagnosis of the fetus was made accordingly. Results: The proband had a 378 kb genomic heterozygous deletion in 1q21.1, which contained RBM8 A and other genes. c.-21G>A mutation was also found in the RBM8 A of the proband. The above-mentioned microdeletion and mutation were inherited from the mother and father, respectively. Prenatal CMA suggested that the fetus carried a 378 kb microdeletion in 1q21.1, and DNA testing did not find c.-21G>A mutation. Conclusion: The heterozygous deletion in 1q21.1 and RBM8 A: c.-21G>A is considered to be the genetic etiology of TAR syndrome in the family. The study provides information for subsequent family genetic counseling and prenatal diagnosis.


Assuntos
Rádio (Anatomia) , Trombocitopenia , Deleção Cromossômica , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Humanos , Gravidez , Diagnóstico Pré-Natal , Rádio (Anatomia)/diagnóstico por imagem , Trombocitopenia/genética , Deformidades Congênitas das Extremidades Superiores
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(6): 569-572, 2021 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-34096028

RESUMO

OBJECTIVE: To assess the value of chromosomal microarray analysis (CMA) to verify a fetus with partial 18p deletion signaled by non-invasive prenatal testing. METHODS: G-banding chromosomal karyotyping analysis was carried out on amniotic fluid sample of the fetus and peripheral blood samples from the parents. Amniotic DNA was also subjected to CMA analysis. The fetus was also subjected to systematic ultrasound scan. RESULTS: The fetus was found to have a karyotype of 46,XX,18p+. CMA has revealed a 5 Mb deletion at 18p11.32-p11.31, a 2.9 Mb duplication at 18p11.31-p11.23, and a 2.5 Mb duplication at 18p11.23-p11.22. No chromosomal aberration or microdeletion/microduplication was detected in either parent. CONCLUSION: Non-invasive prenatal testing and CMA are both sensitive for the detection of chromosomal microdeletions and microduplications. CMA can help with clarification of genotype-phenotype correlation and facilitate prenatal diagnosis and genetic counseling for the family.


Assuntos
Deleção Cromossômica , Diagnóstico Pré-Natal , Cromossomos , Feminino , Feto , Humanos , Cariotipagem , Gravidez
14.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071723

RESUMO

Pathogenic copy number variations (CNVs) contribute to the etiology of neurodevelopmental/neuropsychiatric disorders (NDs). Increased CNV burden has been found to be critically involved in NDs compared with controls in clinical studies. The 1q21.1 CNVs, rare and large chromosomal microduplications and microdeletions, are detected in many patients with NDs. Phenotypes of duplication and deletion appear at the two ends of the spectrum. Microdeletions are predominant in individuals with schizophrenia (SCZ) and microcephaly, whereas microduplications are predominant in individuals with autism spectrum disorder (ASD) and macrocephaly. However, its complexity hinders the discovery of molecular pathways and phenotypic networks. In this review, we summarize the recent genome-wide association studies (GWASs) that have identified candidate genes positively correlated with 1q21.1 CNVs, which are likely to contribute to abnormal phenotypes in carriers. We discuss the clinical data implicated in the 1q21.1 genetic structure that is strongly associated with neurodevelopmental dysfunctions like cognitive impairment and reduced synaptic plasticity. We further present variations reported in the phenotypic severity, genomic penetrance and inheritance.


Assuntos
Anormalidades Múltiplas/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Megalencefalia/genética , Transtornos Mentais/genética , Transtorno do Espectro Autista/genética , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 1/genética , Estudo de Associação Genômica Ampla , Humanos , Microcefalia/genética , Doenças Neurodegenerativas/genética , Transtornos do Neurodesenvolvimento/genética , Esquizofrenia/genética
15.
Nat Struct Mol Biol ; 28(6): 487-500, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34117478

RESUMO

Fanconi anemia (FA) is a devastating hereditary disease characterized by bone marrow failure (BMF) and acute myeloid leukemia (AML). As FA-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), ICLs are widely assumed to be the lesions responsible for FA symptoms. Here, we show that FA-mutated cells are hypersensitive to persistent replication stress and that FA proteins play a role in the break-induced-replication (BIR)-like pathway for fork restart. Both the BIR-like pathway and ICL repair share almost identical molecular mechanisms of 53BP1-BRCA1-controlled signaling response, SLX4- and FAN1-mediated fork cleavage and POLD3-dependent DNA synthesis, suggesting that the FA pathway is intrinsically one of the BIR-like pathways. Replication stress not only triggers BMF in FA-deficient mice, but also specifically induces monosomy 7, which is associated with progression to AML in patients with FA, in FA-deficient cells.


Assuntos
Replicação do DNA , Proteínas de Grupos de Complementação da Anemia de Fanconi/fisiologia , Anemia de Fanconi/genética , Aneuploidia , Animais , Transtornos da Insuficiência da Medula Óssea/etiologia , Linhagem Celular Transformada , Galinhas , Quebra Cromossômica , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , DNA Polimerase III/fisiologia , Replicação do DNA/genética , Progressão da Doença , Anemia de Fanconi/metabolismo , Proteínas de Grupos de Complementação da Anemia de Fanconi/deficiência , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Feminino , Células HCT116 , Células HEK293 , Humanos , Hidroxiureia/farmacologia , Leucemia Mieloide Aguda/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Genéticos , Especificidade da Espécie , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/fisiologia , Ubiquitina-Proteína Ligases/fisiologia
16.
Nucleic Acids Res ; 49(11): 6315-6330, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34107024

RESUMO

DNA methylation, chromatin-binding proteins, and DNA looping are common components regulating genomic imprinting which leads to parent-specific monoallelic gene expression. Loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15 is the most common cause of the imprinting overgrowth disorder Beckwith-Wiedemann Syndrome (BWS). Here, we report a familial transmission of a 7.6 kB deletion that ablates the core promoter of KCNQ1. This structural alteration leads to IC2 LOM and causes recurrent BWS. We find that occupancy of the chromatin organizer CTCF is disrupted proximal to the deletion, which causes chromatin architecture changes both in cis and in trans. We also profile the chromatin architecture of IC2 in patients with sporadic BWS caused by isolated LOM to identify conserved features of IC2 regulatory disruption. A strong interaction between CTCF sites around KCNQ1 and CDKN1C likely drive their expression on the maternal allele, while a weaker interaction involving the imprinting control region element may impede this connection and mediate gene silencing on the paternal allele. We present an imprinting model in which KCNQ1 transcription is necessary for appropriate CTCF binding and a novel chromatin conformation to drive allele-specific gene expression.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Fator de Ligação a CCCTC/metabolismo , Cromossomos Humanos Par 11 , Canal de Potássio KCNQ1/genética , Fator de Ligação a CCCTC/fisiologia , Centrômero , Deleção Cromossômica , Feminino , Impressão Genômica , Humanos , Recém-Nascido , Transcrição Genética
17.
Transl Psychiatry ; 11(1): 357, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131099

RESUMO

The 3q29 deletion (3q29Del) confers high risk for schizophrenia and other neurodevelopmental and psychiatric disorders. However, no single gene in this interval is definitively associated with disease, prompting the hypothesis that neuropsychiatric sequelae emerge upon loss of multiple functionally-connected genes. 3q29 genes are unevenly annotated and the impact of 3q29Del on the human neural transcriptome is unknown. To systematically formulate unbiased hypotheses about molecular mechanisms linking 3q29Del to neuropsychiatric illness, we conducted a systems-level network analysis of the non-pathological adult human cortical transcriptome and generated evidence-based predictions that relate 3q29 genes to novel functions and disease associations. The 21 protein-coding genes located in the interval segregated into seven clusters of highly co-expressed genes, demonstrating both convergent and distributed effects of 3q29Del across the interrogated transcriptomic landscape. Pathway analysis of these clusters indicated involvement in nervous-system functions, including synaptic signaling and organization, as well as core cellular functions, including transcriptional regulation, posttranslational modifications, chromatin remodeling, and mitochondrial metabolism. Top network-neighbors of 3q29 genes showed significant overlap with known schizophrenia, autism, and intellectual disability-risk genes, suggesting that 3q29Del biology is relevant to idiopathic disease. Leveraging "guilt by association", we propose nine 3q29 genes, including one hub gene, as prioritized drivers of neuropsychiatric risk. These results provide testable hypotheses for experimental analysis on causal drivers and mechanisms of the largest known genetic risk factor for schizophrenia and highlight the study of normal function in non-pathological postmortem tissue to further our understanding of psychiatric genetics, especially for rare syndromes like 3q29Del, where access to neural tissue from carriers is unavailable or limited.


Assuntos
Deficiência Intelectual , Transcriptoma , Adulto , Criança , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Humanos , Deficiência Intelectual/genética , Fenótipo
18.
Medicine (Baltimore) ; 100(24): e26307, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34128868

RESUMO

INTRODUCTION: 22q13.3 deletion syndrome is a well-known syndrome characterized by typical clinical findings including neonatal hypotonia, absent or severely delayed speech, intellectual disability, and other various features, and detection of a heterozygous deletion of chromosome 22q13.3 with the involvement of at least part of SHANK3. It is reported that 10% to 29% of patients with 22q13.3 deletion syndrome present lymphedema. Protein-losing enteropathy (PLE) has never been reported in 22q13.3 deletion syndrome. PATIENT CONCERNS: The patient presented to our institution for refractory hypoalbuminemia and chronic lymphedema in both legs. DIAGNOSIS: The patient manifested intellectual disability, absent speech, tooth grinding, dysmorphic face, and abnormal hands and toenails. Copy-number variation sequencing confirmed the maternal deletion in 22q13.31-q13.33 (chr22:46285592-51244566, hg19). The patient was genetically diagnosed with 22q13.3 deletion syndrome. INTERVENTIONS: Low-fat diets and medium-chain triglycerides supplements were prescribed. The patient was recommended to wear compression garments and elevate legs. OUTCOMES: The symptom of diarrhea was resolved, but hypoalbuminemia persisted. Lower extremities lymphedema was gradually becoming severe. CONCLUSIONS: Primary lymphedema and PLE can occur simultaneously in a patient with 22q13.3 deletion syndrome. The 2 phenotypes could share the same genetic etiology of congenital lymphatic abnormalities. CELSR1 deletion may play a role in lymphatic dysplasia. The case also provides additional proof of the pathogenic effect of CELSR1 on hereditary lymphedema.


Assuntos
Caderinas/genética , Transtornos Cromossômicos/genética , Linfedema/genética , Enteropatias Perdedoras de Proteínas/genética , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Hipoalbuminemia/genética , Deficiência Intelectual/genética , Perna (Membro)/patologia , Adulto Jovem
19.
Medicine (Baltimore) ; 100(18): e25777, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950970

RESUMO

RATIONALE: The chromosome 18p deletion syndrome is a syndrome with a deletion of all or a portion of the short arm of the chromosome 18. The phenotypes of the chromosome 18p deletion syndrome vary widely among individuals due to differences in size and breakpoints and the involved genes on the deletions. Given the varied and untypical clinical presentation of this syndrome, the prenatal diagnosis of the syndrome still presents as a challenge. PATIENT CONCERNS: We described 4 China cases with different chromosomal breakpoints. In case 1, a woman who with mild phenotypes gave birth to a severely deformed fetus. Three other cases were for prenatal diagnosis. Their phenotypes are the increased nuchal translucency (INT) and the noninvasive prenatal testing (NIPT) indicated deletions on the chromosome 18p and severe hydronephrosis respectively. DIAGNOSIS: The 4 cases were diagnosed with chromosome 18p deletion syndrome through karyotype analysis and array-based comparative genomic hybridization (array-CGH). INTERVENTIONS: Karyotype analysis and array-based comparative genomic hybridization were used to analyze the abnormal chromosome. OUTCOMES: Case 1 and case 2 revealed 11.51 and 12.39 Mb deletions in 18p11.32p11.21. Case 3 revealed 7.1 Mb deletions in 18p11.3218p11.23. Case 4 revealed 9.9 Mb deletions in 18p11.3218p11.22. LESSONS: In our report, we are the first to report that mother and progeny who have the same chromosomal breakpoint have different phenotypes, significantly. In addition, we found a new phenotype of chromosome 18p deletion syndrome in fetus, which can enrich the phenotypes of this syndrome in the prenatal diagnosis. Finally, we demonstrate that the individuals with different chromosomal breakpoints of 18p deletion syndrome have different phenotypes. On the other hand, the individuals with the same chromosomal breakpoints of 18p deletion syndrome may also have remarkably different phenotypes.


Assuntos
Cariótipo Anormal , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 18/genética , Feto/anormalidades , Hidronefrose/diagnóstico , Adulto , Deleção Cromossômica , Transtornos Cromossômicos/genética , Feminino , Feto/diagnóstico por imagem , Humanos , Hidronefrose/genética , Cariotipagem , Teste Pré-Natal não Invasivo , Medição da Translucência Nucal , Gravidez , Índice de Gravidade de Doença
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(5): 477-480, 2021 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-33974260

RESUMO

OBJECTIVE: To carry out prenatal diagnosis for a fetus with partial 18p deletion detected by non-invasive prenatal testing (NIPT). METHODS: Peripheral blood and amniotic fluid samples of the pregnant woman and her husband were subjected to G-banded chromosomal karyotyping and more accurate chromosomal microarray analysis (CMA). The deletion sites were verified by fluorescence in situ hybridization (FISH) using centromeric probe Cep11 Aqua and telomeric probes Tel11q SO and Tel18 SG. RESULTS: The karyotype of the fetus was determined as 46,XN,del(18)(p11.3). CMA has detected a 6.66 Mb deletion at 18p11.32-p11.31 (136 226-6 796 178). FISH confirmed the presence of a partial deletion at 18p. The mother was found to harbor the same deletion by chromosomal karyotyping as well as CMA analysis. No abnormality was found with the husband. CONCLUSION: Although the fetus and its mother have both carried the same 18p deletion, no clinical manifestation was detected in the mother, which may be attributed to a low penetrance of the disorder. The fetus had died at 33 weeks of gestation with unknown cause.


Assuntos
Deleção Cromossômica , Testes Genéticos , Feminino , Feto , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Gravidez , Diagnóstico Pré-Natal
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