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International Angiology : a Journal of... Apr 2019Vascular anomalies encompass an extremely heterogeneous group of congenital abnormalities of the vascular system. They include vascular tumors and malformations and have... (Review)
Review
INTRODUCTION
Vascular anomalies encompass an extremely heterogeneous group of congenital abnormalities of the vascular system. They include vascular tumors and malformations and have a prevalence of 4.5%. Vascular anomalies are frequently sporadic and associated with somatic mutations and/or a double-hit mechanism and are characterized by considerable phenotypic and genetic heterogeneity. The aim of this review was to provide a genetic description of vascular anomalies, the sequencing technologies used for their diagnosis and the drugs that may potentially be used for their treatment.
EVIDENCE ACQUISITION
PubMed, OMIM, Orphanet, Genetic Testing Registry and ClinicalTrials.gov were searched for monogenic vascular anomalies in order to evaluate the genetic tests (based on sequencing) currently used for their diagnosis, and for any drugs that could be useful to treat them.
EVIDENCE SYNTHESIS
From the search of the clinical synopsis section of OMIM and PubMed for vascular anomalies we selected 19 disorders with a known molecular etiology. From the search for pharmacological trials and therapies in the ClinicalTrials.gov and PubMed databases we selected 87 drugs.
CONCLUSIONS
Most genetic tests with validated clinical utility are based on a next generation sequencing (NGS) approach. Targeted NGS is indeed the best approach for the analysis of disorders with complex phenotypes and genetics and involvement of somatic mutations. Genetic diagnosis provides data for determine genotype-phenotype correlations, segregation and recurrence risk in families, and new targets for gene- or mutation-specific pharmacological therapies. Improvement of diagnostic techniques is needed to offer patients appropriate care, more focused follow-up, and hopefully drugs to treat their disorders.
Topics: Genetic Association Studies; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Vascular Malformations
PubMed: 30938497
DOI: 10.23736/S0392-9590.19.04154-3 -
Birth Defects Research Jan 2018Postaxial polydactyly, type B is the most common type of polydactyly. The vestigial sixth finger is attached by a narrow neurovascular pedicle to the lateral aspect of...
BACKGROUND
Postaxial polydactyly, type B is the most common type of polydactyly. The vestigial sixth finger is attached by a narrow neurovascular pedicle to the lateral aspect of the hand or foot at the level of the metacarpal-phalangeal joint or the metatarsal-phalangeal joint. The occurrence of this type of polydactyly varies among racial groups, by sex and sidedness. Postaxial polydactyly, type A is a fully developed extra digit on the lateral aspect of the hand or foot with a bifid fifth or sixth metacarpal/metatarsal and is much less common.
METHODS
In a malformations surveillance program, the frequency in racial groups, sex ratio and the frequency of other anomalies can be established.
RESULTS
Five hundred forty-five affected infants were identified from 1972 to 2012 in the surveillance of 289,365 liveborn and stillborn infants and elective terminations because of fetal anomalies detected prenatally. Postaxial polydactyly, type B was an isolated anomaly in 95% of the affected newborns. There were more affected males than females. Black infants were affected more often than White infants: 0.91/100 vs. 0.035/100 infants. The dangling extra digit was much more common in the hands than in the feet.
CONCLUSIONS
Postaxial polydactyly, type B is almost always an isolated, mild malformation with no medical significance. Postaxial polydactyly, types B and A occurred in several infants, suggesting that either the underlying mutation(s) can cause both types of postaxial polydactyly or that some affected infants have more than one mutation. Autosomal dominant inheritance with variable expressivity is postulated.
Topics: Female; Fingers; Foot; Foot Deformities, Congenital; Hand; Hand Deformities, Congenital; Humans; Infant; Infant, Newborn; Male; Metacarpophalangeal Joint; Metatarsal Bones; Polydactyly; Toes
PubMed: 29377639
DOI: 10.1002/bdr2.1184 -
American Journal of Human Genetics Apr 2019Structural variation, composed of balanced and unbalanced genomic rearrangements, is an important contributor to human genetic diversity with prominent roles in somatic... (Review)
Review
Structural variation, composed of balanced and unbalanced genomic rearrangements, is an important contributor to human genetic diversity with prominent roles in somatic and congenital disease. At the nucleotide level, structural variants (SVs) have been shown to frequently harbor additional breakpoints and copy-number imbalances, a complexity predicted to emerge wholly as a single-cell division event. Chromothripsis, chromoplexy, and chromoanasynthesis, collectively referred to as chromoanagenesis, are three major mechanisms that explain the occurrence of complex germline and somatic SVs. While chromothripsis and chromoplexy have been shown to be key signatures of cancer, chromoanagenesis has been detected in numerous cases of developmental disease and phenotypically normal individuals. Such observations advocate for a deeper study of the polymorphic and pathogenic properties of complex germline SVs, many of which go undetected by traditional clinical molecular and cytogenetic methods. This review focuses on congenital chromoanagenesis, mechanisms leading to occurrence of these complex rearrangements, and their impact on chromosome organization and genome function. We highlight future applications of routine screening of complex and balanced SVs in the clinic, as these represent a potential and often neglected genetic disease source, a true "iceberg under water."
Topics: Chromosome Aberrations; Chromothripsis; Congenital Abnormalities; Cytogenetic Analysis; Gene Rearrangement; Genome, Human; Genomics; Humans; Karyotyping; Oligonucleotide Array Sequence Analysis; Phenotype
PubMed: 30951674
DOI: 10.1016/j.ajhg.2019.02.024 -
Archives of Gynecology and Obstetrics Sep 2023The aim of this meta-analysis was to evaluate the risk of chromosomal abnormalities in fetuses with congenital heart disease (CHD). (Meta-Analysis)
Meta-Analysis Review
PURPOSE
The aim of this meta-analysis was to evaluate the risk of chromosomal abnormalities in fetuses with congenital heart disease (CHD).
METHODS
Four literature databases were searched until 17th January 2022 using the relevant medical subject heading terms, word variants, and keywords for "congenital heart defect, fetal, and chromosomal abnormalities". The prevalence of overall chromosomal abnormality, aneuploidy, 22q11 deletion, other copy number variants (CNVs), and variants of unknown significance (VOUS) was analyzed.
RESULTS
45 studies met the inclusion criteria for the analysis. The pooled proportion of overall chromosomal abnormalities, aneuploidy, 22q11 deletion, and other CNVs in fetuses with CHD was 23% (95% CI: 20-26%), 19% (95% CI, 16-22%), 2% (95% CI, 2-3%), and 4% (95% CI, 3-5%), respectively. The incidence of overall chromosomal abnormalities, aneuploidy, and other CNVs in non-isolated CHD was higher than in isolated CHD, with odds ratios of 3.08, 3.45, and 4.02, respectively. The incidence of overall chromosomal abnormalities in septal defects was higher than in conotruncal defects and other defects, with odds ratios of 1.60 and 3.61, respectively. In addition, the pooled proportion of VOUS in CHD was 4%.
CONCLUSION
CHD is commonly associated with chromosomal abnormalities. If karyotyping or fluorescence in situ hybridization is normal, chromosomal microarray should be performed to look for submicroscopic abnormalities, especially in fetuses with non-isolated CHD and septal defects.
Topics: Pregnancy; Female; Humans; In Situ Hybridization, Fluorescence; Chromosome Aberrations; Heart Defects, Congenital; Aneuploidy; Fetus; Prenatal Diagnosis
PubMed: 36609702
DOI: 10.1007/s00404-023-06910-3 -
Mutation Research Jul 2016The recent demonstration that massive scale chromosomal shattering or pulverization can occur abruptly due to errors induced by interference with the microtubule... (Review)
Review
The recent demonstration that massive scale chromosomal shattering or pulverization can occur abruptly due to errors induced by interference with the microtubule machinery of the mitotic spindle followed by haphazard chromosomal annealing, together with sophisticated insights from epigenetics, provide profound mechanistic insights into some of the most perplexing classical observations of addiction medicine, including cancerogenesis, the younger and aggressive onset of addiction-related carcinogenesis, the heritability of addictive neurocircuitry and cancers, and foetal malformations. Tetrahydrocannabinol (THC) and other addictive agents have been shown to inhibit tubulin polymerization which perturbs the formation and function of the microtubules of the mitotic spindle. This disruption of the mitotic machinery perturbs proper chromosomal segregation during anaphase and causes micronucleus formation which is the primary locus and cause of the chromosomal pulverization of chromothripsis and downstream genotoxic events including oncogene induction and tumour suppressor silencing. Moreover the complementation of multiple positive cannabis-cancer epidemiological studies, and replicated dose-response relationships with established mechanisms fulfils causal criteria. This information is also consistent with data showing acceleration of the aging process by drugs of addiction including alcohol, tobacco, cannabis, stimulants and opioids. THC shows a non-linear sigmoidal dose-response relationship in multiple pertinent in vitro and preclinical genotoxicity assays, and in this respect is similar to the serious major human mutagen thalidomide. Rising community exposure, tissue storage of cannabinoids, and increasingly potent phytocannabinoid sources, suggests that the threshold mutagenic dose for cancerogenesis will increasingly be crossed beyond the developing world, and raise transgenerational transmission of teratogenicity as an increasing concern.
Topics: Cannabinoids; Cell Cycle Checkpoints; Chromothripsis; Congenital Abnormalities; Dose-Response Relationship, Drug; Epigenesis, Genetic; Gametogenesis; Humans; Marijuana Abuse; Micronuclei, Chromosome-Defective; Neoplasms
PubMed: 27208973
DOI: 10.1016/j.mrfmmm.2016.05.002 -
American Journal of Medical Genetics.... Mar 2020Congenital heart disease (CHD) remains the most common birth defect, with an estimated incidence of approximately 1% of all births. The population of adults with CHD is... (Review)
Review
Congenital heart disease (CHD) remains the most common birth defect, with an estimated incidence of approximately 1% of all births. The population of adults with CHD is growing rapidly with advances in medical care. Overall survival to adulthood in the current era estimated to exceed 90%. Genetic causes of CHD can be classified into several broad categories: (a) chromosomal aneuploidy, (b) large chromosomal deletion or duplication, (c) single gene mutation, and (d) copy number variation. However, only 20-30% of CHD cases have an established etiology characterized by either genetic abnormalities or environmental factors. The role of genetics in the field of adult CHD is only increasing. More adult patients with CHD are seeking genetic counseling to understand the etiology of their underlying CHD and the risks to future offspring. A multidisciplinary approach is essential to provide appropriate counseling to patients regarding indications for genetic testing and interpretations of results. Novel advances with precision medicine may soon enable clinicians to individualize therapies for a comprehensive approach to the care of adult patients with CHD.
Topics: Adult; Aneuploidy; Chromosome Deletion; Chromosome Duplication; Congenital Abnormalities; DNA Copy Number Variations; Genetic Diseases, Inborn; Genetic Testing; Heart Defects, Congenital; Humans
PubMed: 32052945
DOI: 10.1002/ajmg.c.31777 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Jun 2021To analyze the clinical characteristics of 170 cases of macrodactyly.
OBJECTIVE
To analyze the clinical characteristics of 170 cases of macrodactyly.
METHODS
Medical records of 170 macrodactyly patients at Beijing Jishuitan Hospital between March 2006 and October 2019, including demographic characteristics, clinical presentations, anatomical distributions, X-rays, pathological findings, and treatments, were reviewed. PIK3CA mutation analyses of 12 patients were also reviewed.
RESULTS
Disease incidence was similar across sex and geographical regions. Multiple-digit involvement was 3.9 times more frequent than single-digit involvement. In upper deformit: ies, the index finger, middle finger and thumb were mostly involved, and the second and third toes were the most affected on the foot. Two digits were affected more often than three digits, with the affected multiple digits were adjacent most time. The cases of progressive macrodactyly, in which the affected digits grew at a faster rate than the unaffected digits, were found more than static type. Most of progressive macrodactyly were noticed at birth. In terms of nerve involvement, affected fingers mostly occurred in the median nerve innervation area (79.4%) accompanied by median nerve and brunches enlargement and fat infiltration, i.e., nerve territory oriented; affected toes mostly occurred in the medial plantar nerve innervation area (89.1%), marked with overgrowth of adipose tissue with a lesser degree of neural overgrowth, i.e., lipomatous. Only 17 cases had comorbid of syndactyly. The metacarpal bones were involved only in progressive type of macrodactyly. Ten of the 12 cases subjected to mutation analysis were positive. Among all tested specimens, mutation levels ranged from 7% to 27%. In terms of tissue sources in which a mutation was found, adipose tissue had the highest mutation detection rate, followed by nerve and skin. All the DNA samples of blood from the 12 mutation-positive patients were negative.
CONCLUSION
Macrodactyly fingers mostly occurred in the median nerve innervation area accompanied by median nerve and brunches enlargement and fat infiltration. The index and middle fingers were mostly involved. Macrodactyly toes mostly occurred in the medial plantar nerve innervation area, marked with overgrowth of adipose tissue with a lesser degree of neural overgrowth. The second and third toes were the most affected on the foot. A high proportion (83%) of isolated macrodactyly patients carry activating PIK3CA mutations. Adipose, nerve, and skin tissues provide the highest PIK3CA mutation detection yield among all types of tissue studied.
Topics: DNA Mutational Analysis; Fingers; Humans; Infant, Newborn; Limb Deformities, Congenital; Mutation; Toes
PubMed: 34145866
DOI: 10.19723/j.issn.1671-167X.2021.03.025 -
BMJ Case Reports Mar 2023Genetic conditions have varied presentations, and one of them is the association with multiple malformation syndrome (MMS), which has a high mortality rate in the...
Genetic conditions have varied presentations, and one of them is the association with multiple malformation syndrome (MMS), which has a high mortality rate in the immediate postnatal period. Here, we describe a neonate born with multiple anomalies-wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes equinovarus, hypoplastic inferior cerebellar vermis, poor reflexes, hypotonia and ventricular septal defect. There was a history of sibling death with similar malformations, pointing towards a genetic aetiology. Clinical exome sequencing yielded the diagnosis of Zellweger syndrome with a rare mutation in gene. Inherited metabolic syndromes frequently masquerade as malformations, but family history of an affected sibling and clinical suspicion aided diagnosis of the infant.
Topics: Infant; Infant, Newborn; Male; Humans; Zellweger Syndrome; Heart Septal Defects, Ventricular; Abnormalities, Multiple; Mutation; Clubfoot
PubMed: 36931687
DOI: 10.1136/bcr-2022-252014 -
Orphanet Journal of Rare Diseases Sep 2014Simpson-Golabi-Behmel syndrome (SGBS) is a rare overgrowth syndrome clinically characterized by multiple congenital abnormalities, pre/postnatal overgrowth, distinctive... (Review)
Review
Simpson-Golabi-Behmel syndrome (SGBS) is a rare overgrowth syndrome clinically characterized by multiple congenital abnormalities, pre/postnatal overgrowth, distinctive craniofacial features, macrocephaly, and organomegaly. Abnormalities of the skeletal system, heart, central nervous system, kidney, and gastrointestinal tract may also be observed. Intellectual disability, early motor milestones and speech delay are sometimes present; however, there are a considerable number of individuals with normal intelligence.
Topics: Abnormalities, Multiple; Arrhythmias, Cardiac; Genetic Diseases, X-Linked; Gigantism; Heart Defects, Congenital; Humans; Intellectual Disability; Mutation
PubMed: 25238977
DOI: 10.1186/s13023-014-0138-0 -
European Journal of Medical Genetics Jan 2020Our objective was to review the phenotypic and genetic characteristics of tetrasomy 5p from the fetal period until adulthood including prenatal diagnostic evaluations. (Review)
Review
OBJECTIVE
Our objective was to review the phenotypic and genetic characteristics of tetrasomy 5p from the fetal period until adulthood including prenatal diagnostic evaluations.
BACKGROUND
Tetrasomy 5p is a rare chromosomal abnormality. Of the 14 reports, most document mosaic tetrasomy 5p resulting from a supernumerary marker chromosome or isochromosome. There is a wide range of phenotypic manifestations with severity related to more proximal breakpoints and the degree of mosaicism.
DESIGN
We conducted a systematic review using Scopus, PubMed Central® and Ovid MEDLINE® from inception through July 1, 2018 for all articles describing tetrasomy 5p. All articles describing the syndrome of tetrasomy 5p were included.
RESULTS
Of the 15 included cases, 13 exhibited mosaic tetrasomy and two had complete tetrasomy identified by amniocentesis. The most common features include seizures (8/11 live births, 73%), hypotonia (7/11 live births, 64%), developmental delay (7/9 cases that reached childhood, 78%), abnormal external ears (6/11 live births, 55%), short stature (6/11 live births, 55%), ventriculomegaly (5/11 live births, 45.5%) and congenital heart defect (6/15 cases, 40%). The clinical phenotype ranged in severity from mild with no defining characteristics to severe with seizures, developmental delay, and multiple congenital anomalies, resulting in early death. Of these 15 cases, only 6 were diagnosed prenatally by prenatal genetic testing (40%) with prenatal ultrasound identifying abnormalities in 4/6 (67%). Confined placental mosaicism (CPM) was diagnosed in six additional cases due to discordance between CVS and amniocentesis results. Four of the five live births returned for evaluation and each showed normal development.
CONCLUSIONS
Fourteen out of 15 (93%) cases of tetrasomy 5p were associated with an abnormal phenotype. Once a diagnosis is made prenatally, a detailed anatomy ultrasound and fetal echocardiogram must be performed to further characterize any structural abnormalities of the fetus and potentially estimate the clinical severity. Caution should be exercised when prenatal diagnosis of mosaic tetrasomy 5p is found by chorionic villus sampling. CVS alone is insufficient to diagnose tetrasomy 5p and needs to be confirmed with amniocentesis. Our review seeks to inform clinicians on the current literature regarding tetrasomy 5p so that they may better counsel patients when this syndrome is diagnosed.
Topics: Abnormalities, Multiple; Adult; Amniocentesis; Child; Chromosome Disorders; Chromosomes, Human, Pair 5; Developmental Disabilities; Female; Genetic Testing; Humans; In Situ Hybridization, Fluorescence; Isochromosomes; Karyotyping; Male; Mosaicism; Pregnancy; Prenatal Diagnosis; Tetrasomy
PubMed: 30797979
DOI: 10.1016/j.ejmg.2019.02.006