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1.
J Genet ; 1032024.
Artigo em Inglês | MEDLINE | ID: mdl-38831650

RESUMO

Genomic studies make it possible to breakthrough in many fields such as biochemistry, physiology, phylogenetics, etc., though they are unworkable without sequences of genomic DNA of an organism. The terrestrial mollusks' genomes would benefit gastropod biology investigations, that are unavailable so far due to problems in DNA integrity and quality after the isolation procedures. Here we describe a fast and handy protocol for genomic DNA extraction from the tissues of Helix lucorum, which allows to yield high-quality samples applicable for downstream analysis such as high-throughput DNA sequencing. Troubleshooting revealed the nuclease activity of snail tissue lysate, which may be avoided by heating the lysate and decreasing the incubation time.


Assuntos
Deleção Cromossômica , Animais , Humanos , Cromossomos Humanos Par 15/genética , Sequenciamento de Nucleotídeos em Larga Escala , Caracois Helix/genética , Masculino
2.
J Genet ; 1032024.
Artigo em Inglês | MEDLINE | ID: mdl-38831651

RESUMO

In the past, there were no easily distinct and recognizable features as a guide for precise clinical and genetic diagnosis of cases with chromosome microdeletions involving 15q26 including CHD2,. The present study analysed the clinical data and collected venous blood samples from a pediatric patient and his healthy family members for DNA testing. The whole-exome sequencing was performed by the next-generation sequencing (NGS). Chromosomal copy-number variations were tested based on NGS. We present a review of all cases with chromosome microdeletions affecting CHD2. A novel de novo 5.82-Mb deletion at 15q25.3-15q26.1 including CHD2 was identified in our patient who is an 11.6-year-old boy. We first found surprising efficacy of lamotrigine in controlling intractable drop seizures in the individual. These cases have development delay, behavioural problems, epilepsy, variable multiple anomalies, etc. Phenotypes of individuals with deletions involving 15q26 including CHD2 are highly variable with regard to facial features and multiple developmental anomalies. We first found the special clinical entity of development delay, behavioural problems, epilepsy, variable skeletal and muscular anomalies, abnormalities of variable multiple systems and characteristic craniofacial phenotypes in patients with chromosome microdeletions involving CHD2. The larger deletions involving 15q26 including CHD2 tend to cause the classical phenotype. A distinctive craniofacial appearance of the classical phenotype is midface hypoplasia and perifacial protrusion.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 15 , Humanos , Masculino , Criança , Cromossomos Humanos Par 15/genética , Proteínas de Ligação a DNA/genética , Animais , Variações do Número de Cópias de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Fenótipo , Sequenciamento do Exoma , DNA/genética , DNA/isolamento & purificação , Feminino , Análise de Sequência de DNA
3.
Medicine (Baltimore) ; 103(23): e38461, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847723

RESUMO

RATIONALE: With advances in prenatal diagnostic techniques, chromosomal microdeletions and microduplications have become the focus of prenatal diagnosis. 7q partial monosomy or trisomy due to a deletion or duplication of the 7q end is relatively rare and usually originates from parents carrying a balanced translocation. PATIENT CONCERNS: Noninvasive prenatal screening (NIPT) showed a fetus with partial deletion and duplication of chromosome 7q. It was not possible to determine whether the fetus was normal. DIAGNOSES: Conventional chromosome G-banding and chromosome microarray analysis (CMA) were performed on fetal amniotic fluid samples and parental peripheral blood samples. INTERVENTIONS: The pregnant women were given detailed genetic counseling by clinicians. OUTCOMES: The fetal karyotype was 46, XY on conventional G-banding analysis. The CMA test results showed a deletion of approximately 7.8 Mb in the 7q36.1q36.3 region and a duplication of 6.6Mb in the 7q35q36.1 region. The parents' karyotype analysis and CMA results were normal, indicating a new mutation. LESSONS: CMA molecular diagnostic analysis can effectively detect chromosomal microdeletions or microduplications, clarify the relationship between fetal genotype and clinical phenotype, and provide a reference for prenatal diagnosis of chromosomal microdeletion-duplication syndrome.


Assuntos
Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 7 , Diagnóstico Pré-Natal , Humanos , Feminino , Cromossomos Humanos Par 7/genética , Gravidez , Adulto , Duplicação Cromossômica/genética , Diagnóstico Pré-Natal/métodos , Teste Pré-Natal não Invasivo/métodos , Bandeamento Cromossômico , Cariotipagem , Análise em Microsséries/métodos
4.
Biomed Environ Sci ; 37(5): 503-510, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38843923

RESUMO

Objective: VATER/VACTERL-like association is associated with adverse pregnancy outcomes. Genetic evidence of this disorder is sporadic. In this study, we aimed to provide genetic insights to improve the diagnosis of VACTERL. Methods: We have described a Chinese family in which four members were affected by renal defects or agenesis, anal atresia, and anovaginal fistula, which is consistent with the diagnosis of a VACTERL-like association. Pedigree and genetic analyses were conducted using genome and exome sequencing. Results: Segregation analysis revealed the presence of a recessive X-linked microdeletion in two living affected individuals, harboring a 196-380 kb microdeletion on Xq27.1, which was identified by familial exome sequencing. Genome sequencing was performed on the affected male, confirming a -196 kb microdeletion in Xq27.1, which included a 28% loss of the CDR-1 gene. Four family members were included in the co-segregation analysis, and only VACTERL-like cases with microdeletions were reported in X27.1. Conclusion: These results suggest that the 196-380 kb microdeletion in Xq27.1 could be a possible cause of the VATER/VACTERL-like association. However, further genetic and functional analyses are required to confirm or rule out genetic background as the definitive cause of the VACTERL association.


Assuntos
Canal Anal , Cromossomos Humanos X , Linhagem , Adulto , Feminino , Humanos , Masculino , Canal Anal/anormalidades , China , Deleção Cromossômica , Cromossomos Humanos X/genética , População do Leste Asiático/genética , Esôfago/anormalidades , Cardiopatias Congênitas , Rim/anormalidades , Deformidades Congênitas dos Membros/genética , Coluna Vertebral/anormalidades , Traqueia/anormalidades
5.
BMC Urol ; 24(1): 123, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867229

RESUMO

BACKGROUND: Male infertility has become a global health problem, and genetic factors are one of the essential causes. Y chromosome microdeletion is the leading genetic factor cause of male infertility. The objective of this study is to investigate the correlation between male infertility and Y chromosome microdeletions in Hainan, the sole tropical island province of China. METHODS: We analyzed the semen of 897 infertile men from Hainan in this study. Semen analysis was measured according to WHO criteria by professionals at the Department of Reproductive Medicine, the First Affiliated Hospital of Hainan Medical University, where samples were collected. Y chromosome AZF microdeletions were confirmed by detecting six STS markers using multiple polymerase chain reactions on peripheral blood DNA. The levels of reproductive hormones, including FSH, LH, PRL, T, and E2, were quantified using the enzyme-linked immunosorbent assay (ELISA). RESULTS: The incidence of Y chromosome microdeletion in Hainan infertile men was 7.13%. The occurrence rate of Y chromosome microdeletion was 6.69% (34/508) in the oligozoospermia group and 7.71% (30/389) in the azoospermia group. The deletion of various types in the AZF subregion was observed in the group with azoospermia, whereas no AZFb deletion was detected in the oligozoospermia group. Among all patients with microdeletions, the deletion rate of the AZFc region was the higher at 68.75% (44 out of 64), followed by a deletion rate of 6.25% (4 out of 64) for the AZFa region and a deletion rate of 4.69% (3 out of 64) for the AZFb region. The deletion rate of the AZFa region was significantly higher in patients with azoospermia than in patients with oligozoospermia (0.51% vs. 0.39%, p < 0.001). In comparison, the deletion rate of the AZFc region was significantly higher in patients with oligozoospermia (3.08% vs. 6.30%, p < 0.001). Additionally, the AZFb + c subregion association deletion was observed in the highest proportion among all patients (0.89%, 8/897), followed by AZFa + b + c deletion (0.56%, 5/897), and exclusively occurred in patients with azoospermia. Hormone analysis revealed FSH (21.63 ± 2.01 U/L vs. 10.15 ± 0.96 U/L, p = 0.001), LH (8.96 ± 0.90 U/L vs. 4.58 ± 0.42 U/L, p < 0.001) and PRL (263.45 ± 21.84 mIU/L vs. 170.76 ± 17.10 mIU/L, p = 0.002) were significantly increased in azoospermia patients with microdeletions. Still, P and E2 levels were not significantly different between the two groups. CONCLUSIONS: The incidence of AZF microdeletion can reach 7.13% in infertile men in Hainan province, and the deletion of the AZFc subregion is the highest. Although the Y chromosome microdeletion rate is distinct in different regions or populations, the regions mentioned above of the Y chromosome may serve an indispensable role in regulating spermatogenesis. The analysis of Y chromosome microdeletion plays a crucial role in the clinical assessment and diagnosis of male infertility.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Y , Infertilidade Masculina , Técnicas de Reprodução Assistida , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual , Humanos , Masculino , Infertilidade Masculina/genética , Infertilidade Masculina/sangue , Infertilidade Masculina/epidemiologia , China/epidemiologia , Adulto , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/sangue , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/epidemiologia , Hormônio Luteinizante/sangue , Hormônio Foliculoestimulante/sangue , Azoospermia/genética , Azoospermia/sangue , Prolactina/sangue , Oligospermia/genética , Oligospermia/sangue , Testosterona/sangue , Estradiol/sangue , Análise do Sêmen
6.
Transl Psychiatry ; 14(1): 249, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858349

RESUMO

Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the SHANK3 gene. The resulting deficiency of the postsynaptic density scaffolding protein SHANK3 is associated with autism spectrum disorder (ASD). We examined 12 different PMDS patient and CRISPR-engineered stem cell-derived neuronal models and controls and found that reduced expression of SHANK3 leads to neuronal hyperdifferentiation, increased synapse formation, and decreased neuronal activity. We performed automated imaging-based screening of 7,120 target-annotated small molecules and identified three compounds that rescued SHANK3-dependent neuronal hyperdifferentiation. One compound, Benproperine, rescued the decreased colocalization of Actin Related Protein 2/3 Complex Subunit 2 (ARPC2) with ß-actin and rescued increased synapse formation in SHANK3 deficient neurons when administered early during differentiation. Neuronal activity was only mildly affected, highlighting Benproperine's effects as a neurodevelopmental modulator. This study demonstrates that small molecular compounds that reverse developmental phenotypes can be identified in human neuronal PMDS models.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos , Proteínas do Tecido Nervoso , Neurônios , Fenótipo , Sinapses , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transtornos Cromossômicos/genética , Sinapses/efeitos dos fármacos , Cromossomos Humanos Par 22/genética , Masculino , Feminino , Diferenciação Celular/efeitos dos fármacos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Criança
7.
Taiwan J Obstet Gynecol ; 63(3): 398-401, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38802206

RESUMO

OBJECTIVE: We present mosaic distal 10q deletion at prenatal diagnosis in a pregnancy associated with a favorable fetal outcome. CASE REPORT: A 40-year-old, gravida 2, para 0, woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY, del(10) (q26.13)[6]/46,XY[17]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes showed 35% mosaicism for the 10q26.13q26.3 deletion. At 22 weeks of gestation, she underwent cordocentesis which revealed a karyotype of 46,XY,del(10) (q26.13)[16]/46,XY[24]. Prenatal ultrasound findings were normal. At 24 weeks of gestation, she was referred for genetic counseling, and repeat amniocentesis revealed a karyotype of 46,XY,del(10) (q26.13)[4]/46,XY[22]. The parental karyotypes were normal. Molecular genetic analysis on uncultured amniocytes revealed no uniparental disomy (UPD) 10 by quantitative fluorescence polymerase chain reaction (QF-PCR), arr 10q26.13q26.3 × 1.6 (40% mosaicism) by aCGH, and 29.8% (31/104 cells) mosaicism for the distal 10q deletion by interphase fluorescence in situ hybridization (FISH). The woman was advised to continue the pregnancy, and a phenotypically normal 2,900-g male baby was delivered at 39 weeks of gestation. The cord blood had a karyotype of 46,XY,del(10) (q26.13)[6]/46,XY[34], and both the umbilical cord and the placenta had the karyotype of 46,XY. When follow-up at age four months, the neonate was normal in phenotype and development. The peripheral blood had a karyotype of 46,XY,del(10) (q26.13)[5]/46,XY[35], and interphase FISH analysis on buccal mucosal cells showed 8% (8/102 cells) mosaicism for distal 10q deletion. CONCLUSION: Mosaic distal 10q deletion with a normal cell line at prenatal diagnosis can be associated with a favorable fetal outcome and perinatal progressive decrease of the aneuploid cell line.


Assuntos
Amniocentese , Hibridização Genômica Comparativa , Cordocentese , Mosaicismo , Humanos , Gravidez , Feminino , Mosaicismo/embriologia , Adulto , Cromossomos Humanos Par 10/genética , Deleção Cromossômica , Recém-Nascido , Aneuploidia , Cariotipagem
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(6): 753-757, 2024 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-38818564

RESUMO

OBJECTIVE: To carry out genetic analysis on two families with carriers of small terminal translocations using karyotyping analysis and genomic copy number variation sequencing (CNV-seq). METHODS: Two couples undergoing prenatal diagnosis at the Tianjin Central Hospital of Obstetrics and Gynecology respectively on April 12, 2020 and December 17, 2021 were selected as the study subjects. With informed consent, amniotic fluid and peripheral blood samples were collected and subjected to conventional karyotyping and CNV-seq analysis for the detection of chromosomal microdeletion/duplications. RESULTS: Both couples had given births to children with chromosomal aberrations previously, and both fetuses were found to have abnormal karyotypes. CNV-seq showed that they had harbored microdeletion/duplications, and their mothers had both carried balanced translocations involving terminal fragments of chromosomes. CONCLUSION: For fetuses with small chromosomal segmental abnormalities, their parental origin should be traced, and the diagnosis should be confirmed with combined genetic techniques.


Assuntos
Variações do Número de Cópias de DNA , Cariotipagem , Diagnóstico Pré-Natal , Humanos , Diagnóstico Pré-Natal/métodos , Feminino , Gravidez , Masculino , Adulto , Aberrações Cromossômicas , Translocação Genética , Testes Genéticos/métodos , Deleção Cromossômica
9.
Radiology ; 311(2): e233120, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38713025

RESUMO

Background According to 2021 World Health Organization criteria, adult-type diffuse gliomas include glioblastoma, isocitrate dehydrogenase (IDH)-wildtype; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and astrocytoma, IDH-mutant, even when contrast enhancement is lacking. Purpose To develop and validate simple scoring systems for predicting IDH and subsequent 1p/19q codeletion status in gliomas without contrast enhancement using standard clinical MRI sequences. Materials and Methods This retrospective study included adult-type diffuse gliomas lacking contrast at contrast-enhanced MRI from two tertiary referral hospitals between January 2012 and April 2022 with diagnoses confirmed at pathology. IDH status was predicted primarily by using T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign, followed by 1p/19q codeletion prediction. A visual rating of MRI features, apparent diffusion coefficient (ADC) ratio, and relative cerebral blood volume was measured. Scoring systems were developed through univariable and multivariable logistic regressions and underwent calibration and discrimination, including internal and external validation. Results For the internal validation cohort, 237 patients were included (mean age, 44.4 years ± 14.4 [SD]; 136 male patients; 193 patients in IDH prediction and 163 patients in 1p/19q prediction). For the external validation cohort, 35 patients were included (46.1 years ± 15.3; 20 male patients; 28 patients in IDH prediction and 24 patients in 1p/19q prediction). The T2-FLAIR mismatch sign demonstrated 100% specificity and 100% positive predictive value for IDH mutation. IDH status prediction scoring system for tumors without mismatch sign included age, ADC ratio, and morphologic characteristics, whereas 1p/19q codeletion prediction for IDH-mutant gliomas included ADC ratio, cortical involvement, and mismatch sign. For IDH status and 1p/19q codeletion prediction, bootstrap-corrected areas under the receiver operating characteristic curve were 0.86 (95% CI: 0.81, 0.90) and 0.73 (95% CI: 0.65, 0.81), respectively, whereas at external validation they were 0.99 (95% CI: 0.98, 1.0) and 0.88 (95% CI: 0.63, 1.0). Conclusion The T2-FLAIR mismatch sign and scoring systems using standard clinical MRI predicted IDH and 1p/19q codeletion status in gliomas lacking contrast enhancement. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Badve and Hodges in this issue.


Assuntos
Deleção Cromossômica , Isocitrato Desidrogenase , Imageamento por Ressonância Magnética , Mutação , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagem , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Meios de Contraste , Glioma/genética , Glioma/diagnóstico por imagem , Isocitrato Desidrogenase/genética , Imageamento por Ressonância Magnética/métodos , Estudos Retrospectivos
11.
Stem Cell Res ; 77: 103436, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38733811

RESUMO

Y chromosome deletion and karyotype abnormalities are commonly associated with congenital non-obstructive azoospermia, impairing spermatogenesis. Specifically, the deletion of the Y chromosome Azoospermia factor a (AZFa) has been identified in infertile males with severely impaired spermatogenesis. AZFa, encompassing megabase-scale of the Y chromosome region, poses challenges in modeling AZFa deletion-related male infertility using gene editing tools. Here, we successfully created an AZFa-deleted human embryonic stem cell line utilizing the CRISPR/Cas9 gene editing tool. Our analysis indicates the AZFa-deleted stem cell line holds promise for differentiation into ectoderm, mesoderm, and endoderm, highlighting its potential for further comprehensive study.


Assuntos
Células-Tronco Embrionárias Humanas , Humanos , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Masculino , Linhagem Celular , Cromossomos Humanos Y/genética , Diferenciação Celular , Sistemas CRISPR-Cas , Deleção Cromossômica , Edição de Genes
12.
Psychiatr Genet ; 34(3): 71-73, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38690958

RESUMO

Intellectual disability is characterized by impairment in at least two of the following areas: social skills, communication skills, self-care tasks, and academic skills. These impairments are evaluated in relation to the expected standards based on the individual's age and cultural levels. Additionally, intellectual disability is typically defined by a measurable level of intellectual functioning, represented by an intelligence quotients core of 70 or below. Autism spectrum disorder is a developmental disability resulting from differences in the brain, often characterized by problems in social communication and interaction, and limited or repetitive behaviors or interests. Hereditary spherocytosis is a disease characterized by anemia, jaundice, and splenomegaly as a result of increased tendency to hemolysis with morphological transformation of erythrocytes from biconcave disc-shaped cells with central pallor to spherocytes lacking central pallor due to hereditary injury of cellular membrane proteins. An 11-year-old female patient was referred to Pediatric Genetics Subdivision due to the presence of growth retardation and a diagnosis of hereditary spherocytosis. Since she also had dysmorphic facial features, such as frontal bossing, broad and prominent forehead, tubular nasal structure, and thin vermillion, genetic tests were performed. Chromosomal microarray analysis revealed a 2.5 Mb deletion in the 14q23.2q23.3 region. Deletion was also identified in the same region in her father, who had the same phenotypic characteristics, including hereditary spherocytosis and learning difficulties. We propose that the PLEKHG3 and AKAP5 genes, which are located in this region, may contribute to the development of intellectual disability.


Assuntos
Deleção Cromossômica , Haploinsuficiência , Deficiência Intelectual , Humanos , Deficiência Intelectual/genética , Feminino , Criança , Haploinsuficiência/genética , Proteínas de Ancoragem à Quinase A/genética , Esferocitose Hereditária/genética
13.
Clin Epigenetics ; 16(1): 62, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715103

RESUMO

BACKGROUND: Temple syndrome (TS14) is a rare imprinting disorder caused by maternal UPD14, imprinting defects or paternal microdeletions which lead to an increase in the maternal expressed genes and a silencing the paternally expressed genes in the 14q32 imprinted domain. Classical TS14 phenotypic features include pre- and postnatal short stature, small hands and feet, muscular hypotonia, motor delay, feeding difficulties, weight gain, premature puberty along and precocious puberty. METHODS: An exon array comparative genomic hybridization was performed on a patient affected by psychomotor and language delay, muscular hypotonia, relative macrocephaly, and small hand and feet at two years old. At 6 years of age, the proband presented with precocious thelarche. Genes dosage and methylation within the 14q32 region were analyzed by MS-MLPA. Bisulfite PCR and pyrosequencing were employed to quantification methylation at the four known imprinted differentially methylated regions (DMR) within the 14q32 domain: DLK1 DMR, IG-DMR, MEG3 DMR and MEG8 DMR. RESULTS: The patient had inherited a 69 Kb deletion, encompassing the entire DLK1 gene, on the paternal allele. Relative hypermethylation of the two maternally methylated intervals, DLK1 and MEG8 DMRs, was observed along with normal methylation level at IG-DMR and MEG3 DMR, resulting in a phenotype consistent with TS14. Additional family members with the deletion showed modest methylation changes at both the DLK1 and MEG8 DMRs consistent with parental transmission. CONCLUSION: We describe a girl with clinical presentation suggestive of Temple syndrome resulting from a small paternal 14q32 deletion that led to DLK1 whole-gene deletion, as well as hypermethylation of the maternally methylated DLK1-DMR.


Assuntos
Proteínas de Ligação ao Cálcio , Cromossomos Humanos Par 14 , Metilação de DNA , Impressão Genômica , Peptídeos e Proteínas de Sinalização Intercelular , Humanos , Proteínas de Ligação ao Cálcio/genética , Metilação de DNA/genética , Cromossomos Humanos Par 14/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Impressão Genômica/genética , Proteínas de Membrana/genética , Criança , Masculino , Hibridização Genômica Comparativa/métodos , Feminino , Deleção Cromossômica , Pré-Escolar , Fenótipo , Anormalidades Múltiplas/genética , Transtornos da Impressão Genômica , Hipotonia Muscular , Fácies
14.
J Neurodev Disord ; 16(1): 25, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730350

RESUMO

BACKGROUND: Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome. METHODS: We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features. RESULTS: Seizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype-phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers. CONCLUSIONS: These results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype-phenotype relationships when deletion size is taken into account.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 22 , Convulsões , Humanos , Masculino , Feminino , Convulsões/genética , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Cromossomos Humanos Par 22/genética , Criança , Pré-Escolar , Adolescente , Estudos Longitudinais , Adulto Jovem , Adulto , Estudos Prospectivos , Lactente , Proteínas do Tecido Nervoso/genética
15.
Science ; 384(6695): 584-590, 2024 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-38696583

RESUMO

Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22 , Meningomielocele , Animais , Feminino , Humanos , Masculino , Camundongos , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Sequenciamento do Exoma , Ácido Fólico/administração & dosagem , Deficiência de Ácido Fólico/complicações , Deficiência de Ácido Fólico/genética , Meningomielocele/epidemiologia , Meningomielocele/genética , Penetrância , Disrafismo Espinal/genética , Risco , Proteínas Adaptadoras de Transdução de Sinal/genética
16.
Genet Res (Camb) ; 2024: 5549592, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38586596

RESUMO

22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with a broad and heterogeneous phenotype, even though most of the deletions present similar sizes, involving ∼3 Mb of DNA. In a relatively large population of a Brazilian 22q11.2DS cohort (60 patients), we investigated genetic variants that could act as genetic modifiers and contribute to the phenotypic heterogeneity, using a targeted NGS (Next Generation Sequencing) with a specific Ion AmpliSeq panel to sequence nine candidate genes (CRKL, MAPK1, HIRA, TANGO2, PI4KA, HDAC1, ZDHHC8, ZFPM2, and JAM3), mapped in and outside the 22q11.2 hemizygous deleted region. In silico prediction was performed, and the whole-genome sequencing annotation analysis package (WGSA) was used to predict the possible pathogenic effect of single nucleotide variants (SNVs). For the in silico prediction of the indels, we used the genomic variants filtered by a deep learning model in NGS (GARFIELD-NGS). We identified six variants, 4 SNVs and 2 indels, in MAPK1, JAM3, and ZFPM2 genes with possibly synergistic deleterious effects in the context of the 22q11.2 deletion. Our results provide the opportunity for the discovery of the co-occurrence of genetic variants with 22q11.2 deletions, which may influence the patients´ phenotype.


Assuntos
Síndrome de DiGeorge , Humanos , Síndrome de DiGeorge/genética , Fenótipo , Brasil , Deleção Cromossômica
17.
Genome Biol ; 25(1): 95, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622679

RESUMO

BACKGROUND: Aneuploidy, an abnormal number of chromosomes within a cell, is a hallmark of cancer. Patterns of aneuploidy differ across cancers, yet are similar in cancers affecting closely related tissues. The selection pressures underlying aneuploidy patterns are not fully understood, hindering our understanding of cancer development and progression. RESULTS: Here, we apply interpretable machine learning methods to study tissue-selective aneuploidy patterns. We define 20 types of features corresponding to genomic attributes of chromosome-arms, normal tissues, primary tumors, and cancer cell lines (CCLs), and use them to model gains and losses of chromosome arms in 24 cancer types. To reveal the factors that shape the tissue-specific cancer aneuploidy landscapes, we interpret the machine learning models by estimating the relative contribution of each feature to the models. While confirming known drivers of positive selection, our quantitative analysis highlights the importance of negative selection for shaping aneuploidy landscapes. This is exemplified by tumor suppressor gene density being a better predictor of gain patterns than oncogene density, and vice versa for loss patterns. We also identify the importance of tissue-selective features and demonstrate them experimentally, revealing KLF5 as an important driver for chr13q gain in colon cancer. Further supporting an important role for negative selection in shaping the aneuploidy landscapes, we find compensation by paralogs to be among the top predictors of chromosome arm loss prevalence and demonstrate this relationship for one paralog interaction. Similar factors shape aneuploidy patterns in human CCLs, demonstrating their relevance for aneuploidy research. CONCLUSIONS: Our quantitative, interpretable machine learning models improve the understanding of the genomic properties that shape cancer aneuploidy landscapes.


Assuntos
Aneuploidia , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/patologia , Deleção Cromossômica , Cromossomos , Aprendizado de Máquina
18.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(4): 480-485, 2024 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-38565516

RESUMO

OBJECTIVE: To explore the clinical characteristics of 1q21.1 microdeletion by using single nucleotide polymorphism microarrays (SNP array). METHODS: Eighteen cases of 1q21.1 microdeletion syndrome diagnosed at the Longgang District Maternal and Child Health Care Hospital of Shenzhen City from June 2017 to December 2022 were selected as the study subjects. Clinical data of the patients were collected. Results of chromosomal karyotyping and SNP assay were retrospectively analyzed. RESULTS: Among the 18 cases with 1q21.1 microdeletions, 13 had a deletion between BP3 and BP4, 4 had a deletion between BP1/BP2 and BP4, whilst 1 had a proximal 1q21.1 deletion (between BP2 and BP3) involving the Thrombocytopenia-absent radius (TAR) region. The deletions had spanned from 360 kb to 3.9 Mb, which encompassed the GJA5, GJA8, CHD1L, RBM8AB and other morbid genes. In three families, the proband child has inherited the same 1q21.1 microdeletion from their parents, whose clinical phenotype was normal or slightly abnormal. The clinical phenotypes of 1q21.1 microdeletion had included cognitive or behavioral deficits in 9 cases (9/18, 50.0%), growth retardation in 8 cases (8/18, 44.4%), craniofacial deformities in 7 cases (7/18, 38.8%), cardiovascular malformations in 5 cases (5/18, 27.8%), and microcephaly in 3 cases (3/18, 16.7%). CONCLUSION: 1q21.1 microdeletion syndrome has incomplete penetrance and varied expression such as intellectual impairment, growth and development delay, and microcephaly, with a wide range of non-specific phenotypes.


Assuntos
Anormalidades Múltiplas , Deficiência Intelectual , Megalencefalia , Microcefalia , Criança , Humanos , Microcefalia/genética , Estudos Retrospectivos , Deleção Cromossômica , Fenótipo , Biologia Molecular , Deficiência Intelectual/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Cromossomos Humanos Par 1
19.
Exp Hematol ; 134: 104217, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38649131

RESUMO

SAMD9 and SAMD9L are two interferon-regulated genes located adjacent to each other on chromosome 7q21.2. Germline gain-of-function (GL GOF) mutations in SAMD9/SAMD9L are the genetic cause of MIRAGE syndrome, ataxia-pancytopenia (ATXPC) syndrome, myeloid leukemia syndrome with monosomy 7 (MLSM7), refractory cytopenia of childhood (RCC), transient monosomy 7 in children, SAMD9L-associated autoinflammatory disease (SAAD), and a proportion of inherited aplastic anemia and bone marrow failure syndromes. The myeloid neoplasms associated with GL GOF SAMD9/SAMD9L mutations have been included in the World Health Organization (WHO) 2022 classification. The discovery of SAMD9/SAMD9L-related diseases has revealed some interesting pathobiological mechanisms, such as a high rate of primary somatic compensation, with one of the mechanisms being (transient) monosomy 7 a mechanism also described as "adaption by aneuploidy." The somatic compensation in the blood can complicate the diagnosis of SAMD9/SAMD9L-related disease when relying on hematopoietic tissues for diagnosis. Recently, GL loss-of function (LOF) mutations have been identified in older individuals with myeloid malignancies in accordance with a mouse model of SAMD9L loss that develops a myelodysplastic syndrome (MDS)-like disease late in life. The discovery of SAMD9/SAMD9L-associated syndromes has resulted in a deeper understanding of the genetics and biology of diseases/syndromes that were previously oblivious and thought to be unrelated to each other. Besides giving an overview of the literature, this review wants to also provide some practical guidance for the classification of SAMD9/SAMD9L variants that is complicated by the nonrecurrent nature of these mutations but also by the fact that both GL GOF, as well as loss-of-function mutations, have been identified.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7 , Peptídeos e Proteínas de Sinalização Intracelular , Síndromes Mielodisplásicas , Humanos , Cromossomos Humanos Par 7/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/diagnóstico , Animais , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Supressoras de Tumor/genética
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(5): 617-621, 2024 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-38684312

RESUMO

OBJECTIVE: To explore the characteristics of a fetus with chromosome 1p36 deletion syndrome and 3p26.3p25.2 duplication. METHODS: A pregnant woman who had attended the Genetic Counseling Clinic of Linyi People's Hospital on February 22, 2022 and her fetus were selected as the study subjects. Clinical data were collected. Chromosomal karyotyping, fluorescence in situ hybridization (FISH) and chromosomal microarray analysis (CMA) were carried out for the prenatal diagnosis. RESULTS: Ultrasonography at 24th gestational week revealed that the fetus had ventricular septal defect, single umbilical artery, and slight widening of left lateral ventricle (12 mm). The woman was found to have a karyotype of 46,XX,t(1;3)(p36.22;p25.2), and the result of FISH was t(1;3)(3pter+,1qter+;1pter+,3qter+). The fetus was found to have a karyotype of 46,X?,add(1)(p36), and CMA confirmed that it has a 9.0 Mb deletion at 1p36.33p36.22 and a 12.6 Mb duplication at 3p26.3p25.2. Combining the maternal karyotype, the molecular karyotype of the fetus was determined as 46,X?,der(1)t(1;3)(p36.22;p25.2)mat.arr[hg19]1p36.33p36.22(849467_9882666)×1, 3p26.3p25.2(61892_12699607)×3, with the former known to be associated with 1p36 deletion syndrome. CONCLUSION: The fetus was diagnosed with 1p36 deletion syndrome, and its 1p36.33p36.22 deletion and 3p26.3p25.2 duplication had both derived from the balanced translocation carried by its mother.


Assuntos
Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 3 , Cariotipagem , Diagnóstico Pré-Natal , Humanos , Feminino , Cromossomos Humanos Par 1/genética , Gravidez , Cromossomos Humanos Par 3/genética , Adulto , Trissomia/genética , Trissomia/diagnóstico , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/embriologia , Transtornos Cromossômicos/diagnóstico , Hibridização in Situ Fluorescente , Feto/anormalidades
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