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Advances in Experimental Medicine and... 2024Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest,... (Review)
Review
Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest, which can occur as isolated malformations or as part of multiorgan syndromes. Their etiology is multifactorial and characterized by overlapping genetic causes. In this chapter, we present the different genetic alterations underlying the two diseases, which range from chromosomal abnormalities like aneuploidies and structural mutations to rare single nucleotide variations affecting distinct genes. For example, mutations in the cardiac transcription factors NKX2-5, GATA4, and HAND2 have been identified in isolated TOF cases, while mutations of TBX5 and 22q11 deletion, leading to haploinsufficiency of TBX1, cause Holt-Oram and DiGeorge syndrome, respectively. Moreover, genes involved in signaling pathways, laterality determination, and epigenetic mechanisms have also been found mutated in TOF and/or DORV patients. Finally, genome-wide association studies identified common single nucleotide polymorphisms associated with the risk for TOF.
Topics: Humans; Tetralogy of Fallot; Double Outlet Right Ventricle; Mutation; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Transcription Factors
PubMed: 38884738
DOI: 10.1007/978-3-031-44087-8_36 -
BMC Medical Genomics Feb 2018The usage of Artificial Neural Networks (ANNs) for genome-enabled classifications and establishing genome-phenotype correlations have been investigated more extensively...
Application of Neural Networks for classification of Patau, Edwards, Down, Turner and Klinefelter Syndrome based on first trimester maternal serum screening data, ultrasonographic findings and patient demographics.
BACKGROUND
The usage of Artificial Neural Networks (ANNs) for genome-enabled classifications and establishing genome-phenotype correlations have been investigated more extensively over the past few years. The reason for this is that ANNs are good approximates of complex functions, so classification can be performed without the need for explicitly defined input-output model. This engineering tool can be applied for optimization of existing methods for disease/syndrome classification. Cytogenetic and molecular analyses are the most frequent tests used in prenatal diagnostic for the early detection of Turner, Klinefelter, Patau, Edwards and Down syndrome. These procedures can be lengthy, repetitive; and often employ invasive techniques so a robust automated method for classifying and reporting prenatal diagnostics would greatly help the clinicians with their routine work.
METHODS
The database consisted of data collected from 2500 pregnant woman that came to the Institute of Gynecology, Infertility and Perinatology "Mehmedbasic" for routine antenatal care between January 2000 and December 2016. During first trimester all women were subject to screening test where values of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (β-hCG) were measured. Also, fetal nuchal translucency thickness and the presence or absence of the nasal bone was observed using ultrasound.
RESULTS
The architectures of linear feedforward and feedback neural networks were investigated for various training data distributions and number of neurons in hidden layer. Feedback neural network architecture out performed feedforward neural network architecture in predictive ability for all five aneuploidy prenatal syndrome classes. Feedforward neural network with 15 neurons in hidden layer achieved classification sensitivity of 92.00%. Classification sensitivity of feedback (Elman's) neural network was 99.00%. Average accuracy of feedforward neural network was 89.6% and for feedback was 98.8%.
CONCLUSION
The results presented in this paper prove that an expert diagnostic system based on neural networks can be efficiently used for classification of five aneuploidy syndromes, covered with this study, based on first trimester maternal serum screening data, ultrasonographic findings and patient demographics. Developed Expert System proved to be simple, robust, and powerful in properly classifying prenatal aneuploidy syndromes.
Topics: Adolescent; Adult; Computational Biology; Demography; Down Syndrome; Female; Humans; Klinefelter Syndrome; Male; Middle Aged; Mothers; Neural Networks, Computer; Pregnancy; Pregnancy Trimester, First; Prenatal Diagnosis; Trisomy 13 Syndrome; Trisomy 18 Syndrome; Turner Syndrome; Ultrasonography; Young Adult
PubMed: 29439729
DOI: 10.1186/s12920-018-0333-2 -
Ten-year survival of children with trisomy 13 or trisomy 18: a multi-registry European cohort study.Archives of Disease in Childhood Jun 2023To investigate the survival to 10 years of age of children with trisomy 13 (T13) and children with trisomy 18 (T18), born 1995-2014.
OBJECTIVE
To investigate the survival to 10 years of age of children with trisomy 13 (T13) and children with trisomy 18 (T18), born 1995-2014.
DESIGN
Population-based cohort study that linked mortality data to data on children born with T13 or T18, including translocations and mosaicisms, from 13 member registries of EUROCAT, a European network for the surveillance of congenital anomalies.
SETTING
13 regions in nine Western European countries.
PATIENTS
252 live births with T13 and 602 with T18.
MAIN OUTCOME MEASURES
Survival at 1 week, 4 weeks and 1, 5 and 10 years of age estimated by random-effects meta-analyses of registry-specific Kaplan-Meier survival estimates.
RESULTS
Survival estimates of children with T13 were 34% (95% CI 26% to 46%), 17% (95% CI 11% to 29%) and 11% (95% CI 6% to 18%) at 4 weeks, 1 and 10 years, respectively. The corresponding survival estimates were 38% (95% CI 31% to 45%), 13% (95% CI 10% to 17%) and 8% (95% CI 5% to 13%) for children with T18. The 10-year survival conditional on surviving to 4 weeks was 32% (95% CI 23% to 41%) and 21% (95% CI 15% to 28%) for children with T13 and T18, respectively.
CONCLUSIONS
This multi-registry European study found that despite extremely high neonatal mortality in children with T13 and T18, 32% and 21%, respectively, of those who survived to 4 weeks were likely to survive to age 10 years. These reliable survival estimates are useful to inform counselling of parents after prenatal diagnosis.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Child; Trisomy 18 Syndrome; Trisomy 13 Syndrome; Cohort Studies; Prenatal Diagnosis; Registries
PubMed: 36882305
DOI: 10.1136/archdischild-2022-325068 -
Ultrasound in Obstetrics & Gynecology :... Oct 2023To evaluate the impact of detailed late first-trimester ultrasound (LFTU) on the positive predictive value (PPV) of a high-risk non-invasive prenatal test (NIPT) result...
OBJECTIVE
To evaluate the impact of detailed late first-trimester ultrasound (LFTU) on the positive predictive value (PPV) of a high-risk non-invasive prenatal test (NIPT) result for various chromosomal abnormalities.
METHODS
This was a retrospective study of all cases undergoing invasive prenatal testing from three tertiary providers of obstetric ultrasound over 4 years, each using NIPT as a first-line screening test. Data were collected from pre-NIPT ultrasound, NIPT, LFTU, placental serology and later ultrasound examinations. Prenatal testing for chromosomal abnormalities was performed by microarray, initially using array comparative genomic hybridization and then single nucleotide polymorphism (SNP) array for the last 2 years. Uniparental disomy testing was performed by SNP array during all 4 years. The majority of NIPT tests were analyzed using the Illumina platform, initially confined to the assessment of the common autosomal trisomies, sex chromosome aneuploidies and rare autosomal trisomies (RAT), then extending to genome-wide analysis for the last 2 years.
RESULTS
Amniocentesis or chorionic villus sampling (CVS) was performed on 2657 patients, 1352 (51%) of whom had undergone prior NIPT, with 612 (45%) of these returning a high-risk result and meeting the inclusion criteria for the study. LFTU findings significantly affected the PPV of the NIPT result for trisomies 13 (T13), 18 (T18) and 21 (T21), monosomy X (MX) and RAT but not for the other sex chromosomal abnormalities or segmental imbalances (> 7 Mb). Abnormal LFTU increased the PPV close to 100% for T13, T18, T21, MX and RAT. The magnitude of the change in PPV was highest for the most severe chromosomal abnormalities. When LFTU was normal, the incidence of confined placental mosaicism (CPM) was highest in those with a high-risk NIPT result for T13, followed by T18 and T21. After normal LFTU, the PPV for T21, T18, T13 and MX decreased to 68%, 57%, 5% and 25%, respectively.
CONCLUSIONS
LFTU after a high-risk NIPT result can alter the PPV for many chromosomal abnormalities, assisting counseling regarding invasive prenatal testing and pregnancy management. The high PPVs of NIPT for T21 and T18 are not sufficiently modified by normal LFTU findings to alter management. These at-risk patients should be offered CVS for earlier diagnosis, particularly given the low rate of CPM associated with these aneuploidies. Patients with a high-risk NIPT result for T13 and normal LFTU findings often wait for amniocentesis or avoid invasive testing altogether given the low PPV and higher rate of CPM in this context. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Pregnancy; Humans; Female; Pregnancy Trimester, First; Trisomy; Retrospective Studies; Comparative Genomic Hybridization; Placenta; Prenatal Diagnosis; Aneuploidy; Sex Chromosome Aberrations; Trisomy 13 Syndrome
PubMed: 37247395
DOI: 10.1002/uog.26272 -
Prenatal Diagnosis Sep 2023The aim of this study was to describe the incidence of Congenital Diaphragmatic Hernia, CDH, associated with known or clinically suspected syndromes, and the postnatal...
BACKGROUND
The aim of this study was to describe the incidence of Congenital Diaphragmatic Hernia, CDH, associated with known or clinically suspected syndromes, and the postnatal outcomes from a large database for CDH.
METHODS
Data from the multicenter, multinational database on infants with CDH (Congenital Diaphragmatic Hernia Study Group Registry) born from 1996 to 2020 were analyzed. Patients with known or suspected syndromes were grouped and outcome data were analyzed and compared to those without syndromic features.
RESULTS
A total of 12,553 patients were entered in the registry during the study period, and 421 had reported known syndromes, representing 3.4% of all CDH cases in the registry. A total of 50 different associated syndromes were reported. In addition to those with clinically suspected genetic conditions, a total rate of genetic syndromes with CDH was 8.2%. The overall survival to discharge for syndromic CDH was 34% and for non-syndromic CDH was 76.7%. The most common were syndromes Fryns syndrome (19.7% of all syndromes, 17% survival), trisomy 18 or Edward syndrome (17.5%, 9% survival), trisomy 21 or Down syndrome (9%, 47% survival), trisomy 13 or Patau syndrome (6.7%, 14% survival), Cornelia de Lange syndrome (6.4% of all syndromes, 22% survival) and Pallister-Killian syndrome (5.5% of all syndromes, 39.1% survival). In addition, 379 cases had reported chromosomal anomalies and 233 cases had clinically suspected syndromes, based on two more dysmorphic features or malformations in addition to CDH, but without molecular diagnosis. The syndromic CDH group had lower birth weight and gestational age at birth and increased incidence of bilateral CDH (2.9%) and rates of non-repair (53%). The length of hospital stay was longer, and larger number of patients needed O at 30 days. Extracorporeal life support was used only in 15% of the cases. Those who underwent surgical repair had survival to discharge rates of 73%.
CONCLUSION
Syndromic CDH is rare and only 3.4% of the reported cases of CDH have a known syndrome or association, but, if including patients with two dysmorphic features malformations, in addition to CDH, altogether as many as 8.2% have a diagnosed or suspected genetic condition. These children have with lower survival rates. Given higher rates of non-repair and decreased extracorporeal life support use, along with a high early mortality, decision-making regarding goals of care clearly influences outcomes. Survival varies depending on the genetic cause. Early genetic diagnosis is important and may influence the decision-making.
Topics: Infant, Newborn; Infant; Child; Humans; Hernias, Diaphragmatic, Congenital; Incidence; Chromosome Aberrations; Chromosome Disorders; Down Syndrome; Trisomy 18 Syndrome; Trisomy 13 Syndrome; Registries; Retrospective Studies
PubMed: 37418285
DOI: 10.1002/pd.6407 -
BMJ Case Reports Sep 2022A young adolescent girl with trisomy 13 was admitted twice to the paediatric department: the first time because of haematocolpos due to uterus didelphys and unilateral...
A young adolescent girl with trisomy 13 was admitted twice to the paediatric department: the first time because of haematocolpos due to uterus didelphys and unilateral transverse vaginal septum, and the second time because of heart failure due to ruptured sinus of Valsalva aneurysm. As a consequence of the historical early high mortality rate in trisomy 13, we are not aware of known complications in older patients. With better survival nowadays through childhood, we advise structural ultrasonographic cardiac and female genital screening in trisomy 13 patients reaching adolescent age.
Topics: Adolescent; Aged; Aortic Rupture; Child; Female; Hematocolpos; Humans; Sinus of Valsalva; Trisomy 13 Syndrome; Urogenital Abnormalities; Uterus
PubMed: 36150723
DOI: 10.1136/bcr-2021-246514 -
Archivos Peruanos de Cardiologia Y... 2021Most frequent chromosomal syndromes like Down, Patau, Edwards, Turner, and Williams affect the pediatric population in various ways, and congenital heart disease... (Review)
Review
Most frequent chromosomal syndromes like Down, Patau, Edwards, Turner, and Williams affect the pediatric population in various ways, and congenital heart disease explains the altered quality of life they suffer. There is a lack of studies reviewing the cardiac anomalies in these syndromes, and the ones that exist are publications from past decades. We reviewed databases such as MEDLINE, LILACS, SCIELO, and Google Scholar, selecting the best possible evidence, and each chromosomal syndrome was investigated in relation to congenital heart disease, constituting five search groups. The article shows the characteristics of each heart disease described in the studies reviewed, the author, date of publication, country, and population studied, as well as a brief description of the frequency of the disease and its mortality. The results described in this review were contrasted with previous existing literature to verify if there was correspondence between the reported frequencies. The most frequent congenital heart diseases were atrioventricular septal defect (AVSD), ventricular septal defect (VSD), atrial septal defect (ASD), and persistent ductus arteriosus (PDA) in Down syndrome patients, PDA, ASD, and VSD in Patau syndrome patients, AVSD, PDA and valvular defects in Edwards syndrome, bicuspid aortic valve, aortic coarctation and aortic stenosis in Turner syndrome, and supravalvular aortic stenosis and pulmonary stenosis in Williams syndrome.
PubMed: 37727523
DOI: 10.47487/apcyccv.v2i3.155 -
Fetal and Pediatric Pathology Aug 2022Among the many malformations associated with trisomy 13, one of the less recognized is dinosaur tail appendix. We illustrate a dinosaur-tail appendix from an autopsy in...
Among the many malformations associated with trisomy 13, one of the less recognized is dinosaur tail appendix. We illustrate a dinosaur-tail appendix from an autopsy in a newborn female with trisomy 13. This malformation has a frequency between 0.014% and 3.7% in general population. Trisomy 13 is a relatively well-known chromosomal disorder in which dinosaur tail appendix can be found. This entity should be considered element of a complete morphological diagnosis.
Topics: Animals; Appendix; Autopsy; Chromosomes, Human, Pair 13; Dinosaurs; Female; Humans; Trisomy; Trisomy 13 Syndrome
PubMed: 33993843
DOI: 10.1080/15513815.2021.1926020 -
American Journal of Medical Genetics.... Apr 2022The effects of medical and surgical interventions on the survival of patients with trisomy 18 have been reported, leading to changes in perinatal management and...
The effects of medical and surgical interventions on the survival of patients with trisomy 18 have been reported, leading to changes in perinatal management and decision-making. However, few studies have fully reported the recent changes in survival and treatment of trisomy 18. We examined how treatment and survival of patients with trisomy 18 have changed over a decade in a Japanese pediatric tertiary referral center. This retrospective cohort study included patients with trisomy 18 who were admitted within the first 7 days of life at the Hyogo Prefectural Kobe Children's Hospital between 2008 and 2017. The patients were divided into early period (EP) and late period (LP) groups based on the birth year of 2008-2012 and 2013-2017, respectively. Changes in treatment and survival rates were compared between the two groups. A total of 56 patients were studied (29 in the EP group and 27 in the LP group). One-year survival rates were 34.5% and 59.3% in the EP and LP groups, respectively. The survival to discharge rate significantly increased from 27.6% in the EP group to 81.5% in the LP group (p < 0.001). The proportion of patients receiving surgery, especially for congenital heart defects, significantly increased from 59% in the EP group to 96% in the LP group (p = 0.001). In our single-center study, survival and survival to discharge were significantly improved in patients with trisomy 18, probably because of increased rate of surgical interventions. These findings may facilitate better decision-making by patients' families and healthcare providers.
Topics: Child; Female; Heart Defects, Congenital; Humans; Patient Discharge; Pregnancy; Retrospective Studies; Survival Rate; Trisomy; Trisomy 13 Syndrome; Trisomy 18 Syndrome
PubMed: 34889030
DOI: 10.1002/ajmg.a.62605 -
American Journal of Medical Genetics.... Sep 2016The trisomy 13 and trisomy 18 syndromes are important and relatively common chromosome conditions each consisting of a recognizable pattern of multiple congenital... (Review)
Review
The trisomy 13 and trisomy 18 syndromes are important and relatively common chromosome conditions each consisting of a recognizable pattern of multiple congenital anomalies, an increased neonatal and infant mortality, and a marked cognitive and motor disability in older children. Because of the medically serious nature of the outcomes, the traditional approach to management in the newborn and early infancy periods has been to withhold technological support and surgery. In the last decade a rich dialogue has emerged in the literature; one view makes the case for pure comfort care for the benefit of the child while the other view supports full intervention in appropriate situations. The principal aim of the series of articles in this issue of the Seminars in Medical Genetics is to enrich and continue this emerging dialogue. The papers include review articles, original research, and commentaries that discuss perspectives on the care and advances in the management of children with the trisomy 13 and 18 syndromes. © 2016 Wiley Periodicals, Inc.
Topics: Child; Chromosome Disorders; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 18; Disease Management; Humans; Infant; Infant, Newborn; Trisomy; Trisomy 13 Syndrome; Trisomy 18 Syndrome
PubMed: 27643592
DOI: 10.1002/ajmg.c.31527