Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.582
Filtrar
Mais filtros











Intervalo de ano de publicação
1.
J Clin Immunol ; 44(7): 154, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38896123

RESUMO

Patients with chromosome 18q deletion syndrome generally experience hypogammaglobulinemia. Herein, we describe two patients with chromosome 18q deletion syndrome who presented with late-onset combined immune deficiency (LOCID), which has not been previously reported. Patient 1 was a 29-year-old male with 18q deletion syndrome, who was being managed for severe motor and intellectual disabilities at the Yamabiko Medical Welfare Center for 26 years. Although the patient had few infections, he developed Pneumocystis pneumonia at the age of 28. Patient 2, a 48-year-old female with intellectual disability and congenital malformations, was referred to Tokyo Medical and Dental University Hospital with abnormal bilateral lung shadows detected on her chest radiography. Computed tomography showed multiple lymphadenopathies and pneumonia. A lymph node biopsy of the inguinal region revealed granulomatous lymphadenitis, and a chromosomal examination revealed 18q deletion. Array-based genomic hybridization analysis revealed deletion at 18q21.32-q22.3 for patient 1 and at 18q21.33-qter for patient 2. Immune status work-up of the two patients revealed panhypogammaglobulinemia, decreased number of memory B cells and naïve CD4+ and/or CD8+ cells, reduced response on the carboxyfluorescein diacetate succinimidyl ester T-cell division test, and low levels of T-cell receptor recombination excision circles and Ig κ-deleting recombination excision circles. Consequently, both patients were diagnosed with LOCID. Although patients with 18q deletion syndrome generally experience humoral immunodeficiency, the disease can be further complicated by cell-mediated immunodeficiency, causing combined immunodeficiency. Therefore, patients with 18q deletion syndrome should be regularly tested for cellular/humoral immunocompetence.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 18 , Humanos , Masculino , Feminino , Cromossomos Humanos Par 18/genética , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Adulto , Pessoa de Meia-Idade , Idade de Início , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/complicações , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/etiologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/complicações
2.
Medicine (Baltimore) ; 103(10): e37345, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38457559

RESUMO

RATIONALE: Because of the normal phenotype, carriers of specific chromosomal translocations are often diagnosed only after their development of associated malignancies, recurrent miscarriages, and reproductive difficulties. In this paper, we report primary balanced fetal chromosomal translocations by performing the necessary invasive prenatal diagnosis in couples with previous malformations coupled with prenatal testing suggesting a high risk for trisomy 21. PATIENT CONCERNS: Case 1 and Case 2 couples had malformed children, and Case 3 couples had a high risk of trisomy 21 on noninvasive preconception serological testing. DIAGNOSIS AND INTERVENTION: A balanced chromosomal translocation diagnosis was confirmed by karyotyping of fetal cells obtained by amniocentesis. OUTCOMES: All 3 couples decided to continue their pregnancies after learning about the consequences of the chromosomal abnormalities. Approximately a year after the children were born, the staff of the Prenatal Diagnostic Center followed up with a phone call and found that the children physical development and intelligence were normal. LESSON: This case report reports healthy chromosomal balanced translocation newborns born to couples with poor maternal history and couples with abnormalities suggested by preconception testing, and followed up with the newborns to provide some experience in prenatal diagnosis and genetic counseling for chromosomal balanced translocations.


Assuntos
Anormalidades Múltiplas , Transtornos Cromossômicos , Síndrome de Down , Gravidez , Feminino , Criança , Recém-Nascido , Humanos , Translocação Genética , Síndrome de Down/diagnóstico , Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Diagnóstico Pré-Natal , Feto , Anormalidades Múltiplas/genética , Cromossomos
4.
Artigo em Inglês | MEDLINE | ID: mdl-38432776

RESUMO

DNA alterations in gametes, which may occur either spontaneously or as a result of exposure to genotoxicants, can lead to constitutional chromosomal anomalies in the offspring. Alcohol is an established genotoxicant. The goal of this hypothesis-testing longitudinal cohort study was to evaluate the effect of significant/sustained maternal alcohol exposure on clinically diagnosed constitutional chromosomal anomalies among children diagnosed with fetal alcohol syndrome (FAS). De-identified eligibility and claim healthcare records, prospectively generated from the 1990-2012 Florida Medicaid system within the Independent Healthcare Research Database (IHRD), were analyzed. Children examined were continuously eligible with ≥ 8 outpatient office visits during the 96-month period following birth. Among these children, 377 were diagnosed with FAS and 137,135 were not. The incidence rate of chromosomal anomalies involving segregation (trisomy 13, 18, or 21, n = 625), microdeletions (microdeletion syndromes, n = 39), and point mutations (sickle-cell anemia/cystic fibrosis, n = 2570) were examined using frequency risk ratio (RR) and logistic regression (adjusted odds ratio (aOR) for sex, race, residence, socioeconomic/environmental exposure status, and birth date) models. The incidence rates of chromosomal anomalies involving segregation (RR=5.92, aOR=5.85) and microdeletions (RR=41.6, aOR=34.1) were significantly increased in the FAS cohort as compared to the non-diagnosed cohort, but there was no difference in the incidence rate of point mutations (RR=1.14, aOR=1.29). Maternal toxicant exposure should be considered in the etiology of constitutional chromosomal anomaly in offspring.


Assuntos
Transtornos Cromossômicos , Transtornos do Espectro Alcoólico Fetal , Criança , Estados Unidos , Feminino , Gravidez , Humanos , Estudos Longitudinais , Transtornos do Espectro Alcoólico Fetal/epidemiologia , Transtornos do Espectro Alcoólico Fetal/genética , Estudos de Coortes , Aberrações Cromossômicas
5.
Clin Chim Acta ; 557: 117884, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38522821

RESUMO

BACKGROUND: Copy number variation sequencing (CNV-seq) is crucial in prenatal diagnosis, but its limitations in detecting polyploidy, maternal cell contamination (MCC), and uniparental disomy (UPD) restrict its application in the analysis of products of conception (POCs). This study aimed to investigate an optimal genetic testing strategy for POCs in the era of CNV-seq. METHODS: CNV-seq and quantitative fluorescent polymerase chain reaction (QF-PCR) were performed in all 4,211 spontaneous miscarriage cases. Different testing strategies were compared and the optimal testing strategies were proposed. RESULTS: Of the 4,211 cases, 2561 (60.82%) exhibited clinically significant chromosomal abnormalities. CNV-seq alone, without QF-PCR, might misdiagnose 311 (7.39%) cases, including 278 polyploidy, 13 UPD, and 20 MCC. In 20 MCC cases identified by QF-PCR, CNV-seq successfully pinpointed the cause of miscarriage in 13 cases. Furthermore, in cases where QF-PCR suggested polyploidy, CNV-seq improved the diagnostic accuracy in 54 (1.28%) hypo/hypertriploidy cases. After comparing four different strategies, the sequential approach (initiating with CNV-seq followed by QF-PCR if necessary) emerged as advantageous, reducing approximately 70% of the cost associated with QF-PCR while maintaining result accuracy. CONCLUSIONS: We propose an initial CNV-seq followed by QF-PCR if needed-an efficient and cost-effective strategy for the genetic analysis of POCs.


Assuntos
Aborto Espontâneo , Transtornos Cromossômicos , Gravidez , Feminino , Humanos , Transtornos Cromossômicos/genética , Variações do Número de Cópias de DNA/genética , Aborto Espontâneo/diagnóstico , Aborto Espontâneo/genética , Cariotipagem , Aberrações Cromossômicas , Diagnóstico Pré-Natal , Poliploidia
8.
J Pediatr ; 268: 113955, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38340889

RESUMO

OBJECTIVE: To assess rates of cardiac surgery and the clinical and demographic features that influence surgical vs nonsurgical treatment of congenital heart disease (CHD) in patients with trisomy 13 (T13) and trisomy 18 (T18) in the United States. STUDY DESIGN: A retrospective study was performed using the Pediatric Health Information System. All hospital admissions of children (<18 years of age) with T13 and T18 in the United States were identified from 2003 through 2022. International Classifications of Disease (ICD) codes were used to identify presence of CHD, extracardiac comorbidities/malformations, and performance of cardiac surgery. RESULTS: Seven thousand one hundred thirteen patients were identified. CHD was present in 62% (1625/2610) of patients with T13 and 73% (3288/4503) of patients with T18. The most common CHD morphologies were isolated atrial/ventricular septal defects (T13 40%, T18 42%) and aortic hypoplasia/coarctation (T13 21%, T18 23%). Single-ventricle morphologies comprised 6% (100/1625) of the T13 and 5% (167/3288) of the T18 CHD cohorts. Surgery was performed in 12% of patients with T13 plus CHD and 17% of patients with T18 plus CHD. For all cardiac diagnoses, <50% of patients received surgery. Nonsurgical patients were more likely to be born prematurely (P < .05 for T13 and T18). The number of extracardiac comorbidities was similar between surgical/nonsurgical patients with T13 (median 2 vs 2, P = .215) and greater in surgical vs nonsurgical patients with T18 (median 3 vs 2, P < .001). Hospital mortality was <10% for both surgical cohorts. CONCLUSIONS: Patients with T13 or T18 and CHD receive surgical palliation, but at a low prevalence (≤17%) nationally. Given operative mortality <10%, opportunity exists perhaps for quality improvement in the performance of cardiac surgery for these vulnerable patient populations.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Cardiopatias Congênitas , Síndrome da Trissomia do Cromossomo 13 , Síndrome da Trissomía do Cromossomo 18 , Humanos , Estudos Retrospectivos , Estados Unidos/epidemiologia , Feminino , Masculino , Cardiopatias Congênitas/cirurgia , Cardiopatias Congênitas/epidemiologia , Procedimentos Cirúrgicos Cardíacos/métodos , Síndrome da Trissomía do Cromossomo 18/cirurgia , Lactente , Pré-Escolar , Recém-Nascido , Criança , Adolescente , Hospitalização/estatística & dados numéricos , Cromossomos Humanos Par 18 , Trissomia , Transtornos Cromossômicos/epidemiologia
9.
Int J Mol Sci ; 25(4)2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38396741

RESUMO

Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. PWS is characterized by hyperphagia, obesity, low skeletal muscle tone, and autism spectrum disorder (ASD). Oxt also increases muscle tonicity and decreases proteolysis while PWS infants are hypotonic and require assisted feeding in early infancy. This evidence inspired us to merge the results of almost 20 years of studies and formulate a new hypothesis according to which the disruption of Oxt's mechanism of thermoregulation manifests in PWS, SYS, and ASD through thermosensory abnormalities and skeletal muscle tone. This review will integrate the current literature with new updates on PWS, SYS, and ASD and the recent discoveries on Oxt's regulation of thermogenesis to advance the knowledge on these diseases.


Assuntos
Transtorno do Espectro Autista , Regulação da Temperatura Corporal , Transtornos Cromossômicos , Deficiências do Desenvolvimento , Fácies , Hipopituitarismo , Transtornos da Impressão Genômica , Ocitocina , Síndrome de Prader-Willi , Humanos , Lactente , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/metabolismo , Hipotonia Muscular , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/metabolismo
10.
Niger J Clin Pract ; 27(2): 188-193, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38409146

RESUMO

BACKGROUND: Congenital diseases are still an important medical, social, and economic problem all over the world. In North Cyprus, in addition to other reasons, early prenatal diagnostic measures are undertaken to prevent births with thalassemia major, a locally widespread genetic disease. AIM: This study aims to evaluate the results of prenatal invasive diagnostic tests performed in a private obstetrics clinic in Northern Cyprus and show the diagnosis process of thalassemia and chromosomal anomalies. MATERIALS AND METHODS: This study is a retrospective, descriptive study. Chorionic villus sampling (CVS) results and the amniocentesis tests performed between 1990 and 2022 are evaluated. Thalassemia and chromosome analysis of samples obtained by CVS and amniocentesis tests were performed. To diagnose alpha or beta thalassemia and sickle cell, 239 CVS was performed. And to diagnose chromosomal anomalies, 396 CVS and amniocentesis were performed. RESULTS: The mean age of the 480 pregnant women included in the study was 31.12 years (18-46) and 30% of them were older than 34 years. The most common indications for invasive prenatal diagnostic test (IPDT) were; mother/father thalassemia minor/major, advanced maternal age, high risk of ultrasonography erase findings, and the noninvasive screening test. The result of IPDT detected 7.3% chromosomal anomaly and 69.5% thalassemia and sickle cell anemia. Of the 239 CVS performed to diagnose alpha or beta thalasemia and sickle cell, 23.4% beta major, 42.3% beta minor, and 2.1% alpha minor were diagnosed. Of the 396 CVS and amniocentesis performed to diagnose chromosomal anormalies; 2.8% of Down syndrome and 4.54% of other chromosomal anomalies were diagnosed. CONCLUSION: IPDT is important in correctly diagnosing fetal anomalies at the prenatal stage to help families decide at the right time.


Assuntos
Anemia Falciforme , Transtornos Cromossômicos , Talassemia , Gravidez , Feminino , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Chipre , Diagnóstico Pré-Natal/métodos , Amostra da Vilosidade Coriônica , Aberrações Cromossômicas , Testes Diagnósticos de Rotina
11.
J Palliat Med ; 27(4): 503-507, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38387013

RESUMO

Background: The pediatric palliative care (PPC) sets up an interdisciplinary approach of chronic complex diseases throughout birth to adolescence. It encompasses countless contrasts in development and diagnosis scopes, which make this area a challenge to nonpediatric practitioners. Objective: We sought to assess the most prevalent diseases in follow-up of the PPC team. Methods: We analyzed the medical records of PPC clinic during the years 2001 and 2021 and the diagnosis of outpatients. We established a parallel with the world scientific literature concerning the epidemiology of PPC. Results: The most prevalent diseases were epidermolysis bullosa (36.9%), followed by neurological Inherited Errors of Metabolism (IEM) diseases (19.0%), IEM diseases (14.3%), dysmorphological and chromosomal disorders (8.5%), skeletal disorders mainly osteogenesis imperfecta (6.9%), and liver transplantation conditions (5.5%) (p < 0.001). The less frequent conditions were external causes, such as neonatal insults or traffic accidents (2.8%), cancer (1.7%), congenital cardiopathies (1.4%), congenital infectious diseases (1.1%), gastrointestinal and hepatic conditions (0.8%), and rheumatological conditions (0.3%). The patients were older at diagnosis (6.9 years) and at PPC referral (13.2 years) than patients with epidermolysis bullosa and skeletal disorders and dysmorphological and chromosomal disorders were younger on referral. Conclusion: There are a lot of complex chronic conditions which could benefit from palliative care in pediatric setting. However, epidemiological and symptomatological assessment of the health service is necessary to provide an appropriate care to the country's reality.


Assuntos
Transtornos Cromossômicos , Epidermólise Bolhosa , Recém-Nascido , Adolescente , Criança , Humanos , Cuidados Paliativos , Brasil/epidemiologia , Hospitais , Doença Crônica
12.
BMC Pregnancy Childbirth ; 24(1): 23, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38172840

RESUMO

OBJECTIVES: The 15q11.2 BP1-BP2 microdeletion is associated with neurodevelopmental diseases. However, most studies on this microdeletion have focused on adults and children. Thus, in this study, we summarized the molecular characteristics of fetuses with the 15q11.2 BP1-BP2 microdeletion and their postnatal follow-up to guide prenatal diagnosis. METHODS: Ten thousand fetuses were retrospectively subjected to karyotype analysis and chromosome microarray analysis. RESULTS: Chromosome microarray analysis revealed that 37 (0.4%) of the 10,000 fetuses had 15q11.2 BP1-BP2 microdeletions. The fragment size of the 15q11.2 BP1-BP2 region was approximately 312-855 kb and encompassed TUBGCP5, CYFIP1, NIPA2, and NIPA1 genes. Twenty-five of the 37 fetuses with this microdeletion showed phenotypic abnormalities. The most common ultrasonic structural abnormality was congenital heart disease, followed by renal dysplasia and Dandy-Walker malformation. The 15q11.2 BP1-BP2 microdeletion was inherited from the father and mother in 6 and 10 cases, respectively, and de novo inherited in 4 cases. In the postnatal follow-up, 16.1% of the children had postnatal abnormalities. CONCLUSION: Fetuses with the 15q11.2 BP1-BP2 microdeletion showed high proportions of phenotypic abnormalities, but the specificity of penetrance was low. Thus, fetuses with this syndrome are potentially at a higher risk of postnatal growth/behavioral problems and require continuous monitoring of growth and development.


Assuntos
Transtornos Cromossômicos , Deficiência Intelectual , Adulto , Criança , Gravidez , Feminino , Humanos , Estudos Retrospectivos , Seguimentos , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética
13.
BMJ Case Rep ; 17(1)2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38176751

RESUMO

The authors describe a female in her late twenties, presenting with catatonia and diagnosed with epilepsy, autism spectrum disorder, mild intellectual disability, psychosis, dysthymia, anxiety and bipolar disorder, receiving weekly electroconvulsive therapy (ECT). After testing, findings indicated an interstitial deletion in the 22q13.33 region associated with Phelan-McDermid syndrome. In addition, the patient had low cerebral spinal fluid tetrahydrobiopterin (BH4) levels, suggesting dysfunction in the pterin biosynthetic pathway. As a result, the patient started on sapropterin, a BH4 replacement small molecule. After sapropterin treatment, catatonia improved, and the need for ECT decreased. There was an improvement in her cognitive ability, attention and independence. However, there has been no improvement in seizure frequency.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Catatonia , Transtornos Cromossômicos , Transtorno Depressivo Maior , Fenilcetonúrias , Feminino , Humanos , Transtorno do Espectro Autista/complicações , Transtorno Autístico/complicações , Transtorno Autístico/genética , Catatonia/diagnóstico , Catatonia/terapia , Catatonia/complicações , Deleção Cromossômica , Transtornos Cromossômicos/complicações , Cromossomos Humanos Par 22 , Depressão , Transtorno Depressivo Maior/complicações , Fenilcetonúrias/complicações , Adulto
14.
Genes Chromosomes Cancer ; 63(1): e23195, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37548271

RESUMO

Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1. RTPS1 should be evaluated in all individuals with rhabdoid tumor and is more likely in those with a young age at presentation (occasionally congenital presentation), multiple primary tumors, or a family history of rhabdoid tumor or RTPS1. Proband genetic testing is the standard method for diagnosing RTPS1. Most known RTPS1-related SMARCB1 gene mutations are copy number variants (CNVs) or single nucleotide variants/indels, but structural variant analysis (SVA) is not usually included in the molecular evaluation. Here, we report two children with RTPS1 presenting with atypical teratoid/rhabdoid tumor (ATRT) who had constitutional testing showing balanced chromosome translocations involving SMARCB1. Patient 1 is a 23-year-old female diagnosed with pineal region ATRT at 7 months who was found to have a de novo, constitutional t(16;22)(p13.3;q11.2). Patient 2 is a 24-month-old male diagnosed with a posterior fossa ATRT at 14 months, with subsequent testing showing a constitutional t(5;22)(q14.1;q11.23). These structural rearrangements have not been previously reported in RTPS1. While rare, these cases suggest that structural variants should be considered in the evaluation of children with rhabdoid tumors to provide more accurate genetic counseling on the risks of developing tumors, the need for surveillance, and the risks of passing the disorder on to future children. Further research is needed to understand the prevalence, clinical features, and tumor risks associated with RTPS1-related constitutional balanced translocations.


Assuntos
Neoplasias Encefálicas , Transtornos Cromossômicos , Tumor Rabdoide , Teratoma , Criança , Feminino , Masculino , Humanos , Adulto Jovem , Adulto , Lactente , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Neoplasias Encefálicas/genética , Mutação em Linhagem Germinativa , Translocação Genética , Teratoma/genética , Teratoma/patologia
15.
Horm Res Paediatr ; 97(2): 148-156, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37343528

RESUMO

INTRODUCTION: Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder caused by truncating mutations of the MAGEL2 gene, located in the Prader-Willi syndrome (PWS) region. PWS and SYS have phenotypic overlap. Patients with SYS are often treated with growth hormone (GH), but evidence for the effectiveness of the treatment in patients with SYS is limited. METHODS: This study describes 7 children with SYS. We studied their phenotype, genotype, and the effect of GH treatment on height and body mass index (BMI) during 4 years and on body composition during 1 year. RESULTS: All patients had a normal birth weight. Most patients had hypotonia and feeding difficulties after birth (86%). Full-scale IQ ranged from <50 to 92. All patients above the age of 2 years had psycho-behavioral problems. There were no apparent correlations between the phenotype and the location of the defect in the MAGEL2 gene. Mean (95% CI) height SDS increased significantly from -1.74 (-3.55; 0.07) at start to -0.05 (-1.87; 1.77) after 4 years of GH treatment. Mean (95% CI) BMI SDS decreased significantly from 2.01 (1.02; 3.00) to 1.22 (0.18; 2.26) after 6 months and remained the same during the rest of the follow-up. Fat mass percentage SDS decreased and lean body mass did not change during 1 year of treatment in 3 patients. CONCLUSION: Patients presented with a phenotype of hypotonia, respiratory insufficiency, and feeding difficulties after birth, endocrine disorders, intellectual disability, and behavioral problems. Treatment with GH significantly improved height SDS and BMI over the course of 4 years.


Assuntos
Transtornos Cromossômicos , Deficiências do Desenvolvimento , Fácies , Hormônio do Crescimento Humano , Hipopituitarismo , Transtornos da Impressão Genômica , Criança , Pré-Escolar , Humanos , Hormônio do Crescimento Humano/uso terapêutico , Hormônio do Crescimento Humano/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Intrinsicamente Desordenadas/genética , Hipotonia Muscular/tratamento farmacológico , Hipotonia Muscular/genética , Fenótipo , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/genética
16.
Pediatr Nephrol ; 39(3): 749-760, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37733098

RESUMO

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder caused by SHANK3 pathogenic variants or chromosomal rearrangements affecting the chromosome 22q13 region. Previous research found that kidney disorders, primarily congenital anomalies of the kidney and urinary tract, are common in people with PMS, yet research into candidate genes has been hampered by small study sizes and lack of attention to these problems. METHODS: We used a cohort of 357 people from the Phelan-McDermid Syndrome Foundation International Registry to investigate the prevalence of kidney disorders in PMS using a cross-sectional design and to identify 22q13 genes contributing to these disorders. RESULTS: Kidney disorders reported included vesicoureteral reflux (n = 37), hydronephrosis (n = 36), dysplastic kidneys (n = 19), increased kidney size (n = 19), polycystic kidneys (15 cases), and kidney stones (n = 4). Out of 315 subjects with a 22q13 deletion, 101 (32%) had at least one kidney disorder, while only one out of 42 (2%) individuals with a SHANK3 pathogenic variant had a kidney disorder (increased kidney size). We identified two genomic regions that were significantly associated with having a kidney disorder with the peak associations observed near positions approximately 5 Mb and 400 Kb from the telomere. CONCLUSIONS: The candidate genes for kidney disorders include FBLN1, WNT7B, UPK3A, CELSR1, and PLXNB2. This study demonstrates the utility of patient registries for uncovering genetic contributions to rare diseases. Future work should focus on functional studies for these genes to assess their potential pathogenic contribution to the different subsets of kidney disorders.


Assuntos
Transtornos Cromossômicos , Doenças Renais Policísticas , Humanos , Estudos Transversais , Proteínas do Tecido Nervoso/genética , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Deleção Cromossômica , Rim/patologia , Doenças Renais Policísticas/epidemiologia , Doenças Renais Policísticas/genética , Cromossomos Humanos Par 22
17.
HGG Adv ; 5(1): 100256, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-37981762

RESUMO

In this study, we report on mosaic variegated aneuploidy (MVA) syndrome with tetraploidy and predisposition to infertility in a family. Sequencing analysis identified that the CEP192 biallelic variants (c.1912C>T, p.His638Tyr and c.5750A>G, p.Asn1917Ser) segregated with microcephaly, short stature, limb-extremity dysplasia, and reduced testicular size, while CEP192 monoallelic variants segregated with infertility and/or reduced testicular size in the family. In 1,264 unrelated patients, variant screening for CEP192 identified a same variant (c.5750A>G, p.Asn1917Ser) and other variants significantly associated with infertility. Two lines of Cep192 mice model that are equivalent to human variants were generated. Embryos with Cep192 biallelic variants arrested at E7 because of cell apoptosis mediated by MVA/tetraploidy cell acumination. Mice with heterozygous variants replicated the predisposition to male infertility. Mouse primary embryonic fibroblasts with Cep192 biallelic variants cultured in vitro showed abnormal morphology, mitotic arresting, and disruption of spindle formation. In patient epithelial cells with biallelic variants cultured in vitro, the number of cells arrested during the prophase increased because of the failure of spindle formation. Accordingly, we present mutant CEP192, which is a link for the MVA syndrome with tetraploidy and the predisposition to male infertility.


Assuntos
Transtornos Cromossômicos , Infertilidade Masculina , Humanos , Masculino , Camundongos , Animais , Tetraploidia , Aneuploidia , Suscetibilidade a Doenças , Infertilidade Masculina/genética , Proteínas Cromossômicas não Histona/genética , Mosaicismo
18.
Ultrasound Obstet Gynecol ; 63(6): 798-806, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38112514

RESUMO

OBJECTIVES: To compute a set of atypicality indices based on combined first-trimester screening (cFTS) markers and second-trimester estimated fetal weight (EFW), and to demonstrate their potential in identifying pregnancies at reduced or increased risk of chromosomal aberrations following a low-risk cFTS result. METHODS: The atypicality index quantifies the unusualness of an individual set of measurements relative to a reference distribution and can be computed from any variables or measurements available. A score of 0% on the atypicality index represents the most typical profiles, while a score of 100% indicates the highest level of atypicality. From the Danish Fetal Medicine Database, we retrieved data on all pregnant women seen for cFTS in the Central Denmark Region between January 2008 and December 2018. All pregnancies with a cytogenetic or molecular analysis obtained prenatally, postnatally or following pregnancy loss or termination were identified. A first-trimester atypicality index (AcFTS) was computed based on nuchal translucency (NT) thickness, maternal serum free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Furthermore, a second-trimester index (AcFTS + EFW) was computed from cFTS markers and EFW from a routine second-trimester anomaly scan. All pregnancies were stratified into subgroups based on their atypicality levels and their cFTS risk estimates. The risk of chromosomal aberrations in each subgroup was then compared with the overall prevalence, and a graphical presentation of the multivariate measurement profiles was developed. RESULTS: We retrieved data on 145 955 singleton pregnancies, of which 9824 (6.7%) were genetically examined. Overall, 1 in 122 (0.82% (95% CI, 0.77-0.87%)) of all pregnancies seen for cFTS were affected by a fetal chromosomal aberration, and in screen-negative pregnancies (cFTS trisomy 21 risk < 1 in 100 and/or trisomy 18/13 risk < 1 in 50), 0.41% (95% CI, 0.38-0.44%) were affected. In screen-negative pregnancies with a typical first-trimester profile (AcFTS < 80%), the risk of chromosomal aberrations was significantly reduced (0.28%) compared with the overall risk. The risk of chromosomal aberrations increased with higher atypicality index to 0.49% (AcFTS [80-90%)), 1.52% (AcFTS [90-99%)) and 4.44% (AcFTS ≥ 99%) and was significantly increased in the two most atypical subgroups. The same applied for the second-trimester atypicality index, with risks of chromosomal aberrations of 0.76% and 4.16% in the two most atypical subgroups (AcFTS + EFW [90-99%) and AcFTS + EFW ≥ 99%, respectively). CONCLUSIONS: As an add-on to cFTS, the atypicality index identifies women with typical measurement profiles, which may provide reassurance, whereas atypical profiles may warrant specialist referral and further investigation. In pregnancies identified as low risk on cFTS but with a highly atypical distribution of NT, PAPP-A and ß-hCG, the risk of a chromosomal aberration is substantially increased. The atypicality index optimizes the interpretation of pre-existing prenatal screening profiles and is not limited to cFTS markers or EFW. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.


Assuntos
Gonadotropina Coriônica Humana Subunidade beta , Aberrações Cromossômicas , Medição da Translucência Nucal , Primeiro Trimestre da Gravidez , Proteína Plasmática A Associada à Gravidez , Humanos , Feminino , Gravidez , Gonadotropina Coriônica Humana Subunidade beta/sangue , Adulto , Aberrações Cromossômicas/embriologia , Aberrações Cromossômicas/estatística & dados numéricos , Dinamarca/epidemiologia , Proteína Plasmática A Associada à Gravidez/análise , Proteína Plasmática A Associada à Gravidez/metabolismo , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Segundo Trimestre da Gravidez , Diagnóstico Pré-Natal/métodos , Peso Fetal , Biomarcadores/sangue , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/embriologia , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/embriologia
19.
Rev Paul Pediatr ; 42: e2023053, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38088680

RESUMO

OBJECTIVE: To describe the newborn population with Patau (T13) and Edwards Syndrome (T18) with congenital heart diseases that stayed in the Intensive Care Unit (ICU) of a quaternary care hospital complex, regarding surgical and non-surgical medical procedures, palliative care, and outcomes. METHODS: Descriptive case series conducted from January/2014 to December/2018 through analysis of records of patients with positive karyotype for T13 or T18 who stayed in the ICU of a quaternary hospital. Descriptive statistics analysis was applied. RESULTS: 33 records of eligible patients were identified: 27 with T18 (82%), and 6 T13 (18%); 64% female and 36% male. Eight were preterm infants with gestational age between 30-36 weeks (24%), and only 4 among the 33 infants had a birth weight >2500 g (12%). Four patients underwent heart surgery and one of them died. Intrahospital mortality was 83% for T13, and 59% for T18. The majority had other malformations and underwent other surgical procedures. Palliative care was offered to 54% of the patients. The median hospitalization time for T18 and T13 was 29 days (range: 2-304) and 25 days (13-58), respectively. CONCLUSIONS: Patients with T13 and T18 have high morbidity and mortality, and long hospital and ICU stays. Multicentric studies are needed to allow the analysis of important aspects for creating protocols that, seeking therapeutic proportionality, may bring better quality of life for patients and their families.


Assuntos
Transtornos Cromossômicos , Lactente , Humanos , Masculino , Recém-Nascido , Feminino , Síndrome da Trissomía do Cromossomo 18 , Transtornos Cromossômicos/epidemiologia , Síndrome da Trissomia do Cromossomo 13 , Cuidados Paliativos , Qualidade de Vida , Recém-Nascido Prematuro , Hospitais , Trissomia , Estudos Retrospectivos
20.
Nat Commun ; 14(1): 7020, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37919272

RESUMO

Inverted duplications, also known as foldback inversions, are commonly observed in cancers and are the major class of chromosome rearrangement recovered from yeast cells lacking Mre11 nuclease activity. Foldback priming at DNA double-strand breaks (DSBs) is one mechanism proposed for the generation of inverted duplications. However, the other pathway steps have not been fully elucidated. Here, we show that a DSB induced near natural inverted repeats drives high frequency inverted duplication in Sae2 and Mre11-deficient cells. We find that DNA polymerase δ proof-reading activity, but not Rad1 nuclease, trims the heterologous flaps formed after foldback annealing. Additionally, Pol32 is required for the generation of inverted duplications, suggesting that Pol δ catalyzes fill-in synthesis primed from the foldback to create a hairpin-capped chromosome that is subsequently replicated to form a dicentric inversion chromosome. Finally, we show that stabilization of the dicentric chromosome after breakage involves telomere capture by non-reciprocal translocation mediated by repeat sequences or by deletion of one centromere.


Assuntos
Transtornos Cromossômicos , Proteínas de Saccharomyces cerevisiae , Humanos , DNA Polimerase III/genética , DNA Polimerase III/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Inversão Cromossômica/genética , Transtornos Cromossômicos/genética , Cromossomos/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA