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Genes May 2020There is a high incidence of chromosomal abnormalities in early human embryos, whether they are generated by natural conception or by assisted reproductive technologies... (Review)
Review
There is a high incidence of chromosomal abnormalities in early human embryos, whether they are generated by natural conception or by assisted reproductive technologies (ART). Cells with chromosomal copy number deviations or chromosome structural rearrangements can compromise the viability of embryos; much of the naturally low human fecundity as well as low success rates of ART can be ascribed to these cytogenetic defects. Chromosomal anomalies are also responsible for a large proportion of miscarriages and congenital disorders. There is therefore tremendous value in methods that identify embryos containing chromosomal abnormalities before intrauterine transfer to a patient being treated for infertility-the goal being the exclusion of affected embryos in order to improve clinical outcomes. This is the rationale behind preimplantation genetic testing for aneuploidy (PGT-A) and structural rearrangements (-SR). Contemporary methods are capable of much more than detecting whole chromosome abnormalities (e.g., monosomy/trisomy). Technical enhancements and increased resolution and sensitivity permit the identification of chromosomal mosaicism (embryos containing a mix of normal and abnormal cells), as well as the detection of sub-chromosomal abnormalities such as segmental deletions and duplications. Earlier approaches to screening for chromosomal abnormalities yielded a binary result of normal versus abnormal, but the new refinements in the system call for new categories, each with specific clinical outcomes and nuances for clinical management. This review intends to give an overview of PGT-A and -SR, emphasizing recent advances and areas of active development.
Topics: Abortion, Spontaneous; Aneuploidy; Blastocyst; Chromosome Aberrations; Chromosome Disorders; Chromosomes; Humans; Mosaicism; Preimplantation Diagnosis
PubMed: 32485954
DOI: 10.3390/genes11060602 -
The Journal of Clinical Investigation Apr 2024Capillary malformation (CM), or port wine birthmark, is a cutaneous congenital vascular anomaly that occurs in 0.1%-2% of newborns. Patients with a CM localized on the... (Review)
Review
Capillary malformation (CM), or port wine birthmark, is a cutaneous congenital vascular anomaly that occurs in 0.1%-2% of newborns. Patients with a CM localized on the forehead have an increased risk of developing a neurocutaneous disorder called encephalotrigeminal angiomatosis or Sturge-Weber syndrome (SWS), with complications including seizure, developmental delay, glaucoma, and vision loss. In 2013, a groundbreaking study revealed causative activating somatic mutations in the gene (GNAQ) encoding guanine nucleotide-binding protein Q subunit α (Gαq) in CM and SWS patient tissues. In this Review, we discuss the disease phenotype, the causative GNAQ mutations, and their cellular origin. We also present the endothelial Gαq-related signaling pathways, the current animal models to study CM and its complications, and future options for therapeutic treatment. Further work remains to fully elucidate the cellular and molecular mechanisms underlying the formation and maintenance of the abnormal vessels.
Topics: Infant, Newborn; Animals; Humans; Glaucoma; Models, Animal; Mutation; Capillaries; Vascular Malformations
PubMed: 38618955
DOI: 10.1172/JCI172842 -
Orphanet Journal of Rare Diseases Aug 2006Walker-Warburg Syndrome (WWS) is a rare form of autosomal recessive congenital muscular dystrophy associated with brain and eye abnormalities. WWS has a worldwide... (Review)
Review
Walker-Warburg Syndrome (WWS) is a rare form of autosomal recessive congenital muscular dystrophy associated with brain and eye abnormalities. WWS has a worldwide distribution. The overall incidence is unknown but a survey in North-eastern Italy has reported an incidence rate of 1.2 per 100,000 live births. It is the most severe form of congenital muscular dystrophy with most children dying before the age of three years. WWS presents at birth with generalized hypotonia, muscle weakness, developmental delay with mental retardation and occasional seizures. It is associated with type II cobblestone lissencephaly, hydrocephalus, cerebellar malformations, eye abnormalities and congenital muscular dystrophy characterized by hypoglycosylation of alpha-dystroglycan. Several genes have been implicated in the etiology of WWS, and others are as yet unknown. Several mutations were found in the Protein O-Mannosyltransferase 1 and 2 (POMT1 and POMT2) genes, and one mutation was found in each of the fukutin and fukutin-related protein (FKRP) genes. Laboratory investigations usually show elevated creatine kinase, myopathic/dystrophic muscle pathology and altered alpha-dystroglycan. Antenatal diagnosis is possible in families with known mutations. Prenatal ultrasound may be helpful for diagnosis in families where the molecular defect is unknown. No specific treatment is available. Management is only supportive and preventive.
Topics: Abnormalities, Multiple; Brain; Child, Preschool; Dystrophin; Eye Abnormalities; Female; Glycoproteins; Humans; Infant; Infant, Newborn; Mannosyltransferases; Muscular Dystrophies; Mutation; Pregnancy; Prenatal Diagnosis; Prognosis; Syndrome
PubMed: 16887026
DOI: 10.1186/1750-1172-1-29 -
Orphanet Journal of Rare Diseases Oct 2007Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype (high forehead, frontal bossing, large eyebrows,... (Review)
Review
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype (high forehead, frontal bossing, large eyebrows, medially flaring and sparse in the middle part, hypertelorism, deep set but large eyes, large and uplifted ear lobes, with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth, with M-shaped upper lip, frequent smiling, and a prominent but narrow and triangular pointed chin), moderate-to-severe intellectual deficiency, epilepsy and variable congenital malformations including Hirschsprung disease (HSCR), genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies. The prevalence of MWS is currently unknown, but 171 patients have been reported so far. It seems probable that MWS is under-diagnosed, particularly in patients without HSCR. MWS is caused by heterozygous mutations or deletions in the Zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1). To date, over 100 deletions/mutations have been reported in patients with a typical phenotype; they are frequently whole gene deletions or truncating mutations, suggesting that haploinsufficiency is the main pathological mechanism. Studies of genotype-phenotype analysis show that facial gestalt and delayed psychomotor development are constant clinical features, while the frequent and severe congenital malformations are variable. In a small number of patients, unusual mutations can lead to an atypical phenotype. The facial phenotype is particularly important for the initial clinical diagnosis and provides the hallmark warranting ZEB2 mutational analysis, even in the absence of HSCR. The majority of MWS cases reported so far were sporadic, therefore the recurrence risk is low. Nevertheless, rare cases of sibling recurrence have been observed. Congenital malformations and seizures require precocious clinical investigation with intervention of several specialists (including neonatologists and pediatricians). Psychomotor development is delayed in all patients, therefore rehabilitation (physical therapy, psychomotor and speech therapy) should be started as soon as possible.
Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Epilepsy; Female; Genotype; Hirschsprung Disease; Homeodomain Proteins; Humans; Infant; Intellectual Disability; Male; Maxillofacial Abnormalities; Mutation; Phenotype; Prognosis; Repressor Proteins; Syndrome; Zinc Finger E-box Binding Homeobox 2
PubMed: 17958891
DOI: 10.1186/1750-1172-2-42 -
Cell Cycle (Georgetown, Tex.) Jan 2013"RASopathies" are a group of developmental syndromes with partly overlapping clinical symptoms that are caused by germline mutations of genes within the Ras/MAPK... (Review)
Review
"RASopathies" are a group of developmental syndromes with partly overlapping clinical symptoms that are caused by germline mutations of genes within the Ras/MAPK signaling pathway. Mutations affecting this pathway can also occur in a mosaic state, resulting in congenital syndromes often distinct from those generated by the corresponding germline mutations. For syndromes caused by mosaic mutations of the Ras/MAPK signaling pathway, the term "mosaic RASopathies" has been proposed. In the following article, genetic and phenotypic aspects of mosaic RASopathies will be discussed.
Topics: Congenital Abnormalities; Extracellular Signal-Regulated MAP Kinases; Germ-Line Mutation; Humans; Mitogen-Activated Protein Kinase Kinases; Mosaicism; Neoplasms; Signal Transduction; Syndrome; raf Kinases; ras Proteins
PubMed: 23255105
DOI: 10.4161/cc.23108 -
Orphanet Journal of Rare Diseases Sep 2006CHARGE syndrome was initially defined as a non-random association of anomalies (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital... (Review)
Review
CHARGE syndrome was initially defined as a non-random association of anomalies (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness). In 1998, an expert group defined the major (the classical 4C's: Choanal atresia, Coloboma, Characteristic ears and Cranial nerve anomalies) and minor criteria of CHARGE syndrome. Individuals with all four major characteristics or three major and three minor characteristics are highly likely to have CHARGE syndrome. However, there have been individuals genetically identified with CHARGE syndrome without the classical choanal atresia and coloboma. The reported incidence of CHARGE syndrome ranges from 0.1-1.2/10,000 and depends on professional recognition. Coloboma mainly affects the retina. Major and minor congenital heart defects (the commonest cyanotic heart defect is tetralogy of Fallot) occur in 75-80% of patients. Choanal atresia may be membranous or bony; bilateral or unilateral. Mental retardation is variable with intelligence quotients (IQ) ranging from normal to profound retardation. Under-development of the external genitalia is a common finding in males but it is less apparent in females. Ear abnormalities include a classical finding of unusually shaped ears and hearing loss (conductive and/or nerve deafness that ranges from mild to severe deafness). Multiple cranial nerve dysfunctions are common. A behavioral phenotype for CHARGE syndrome is emerging. Mutations in the CHD7 gene (member of the chromodomain helicase DNA protein family) are detected in over 75% of patients with CHARGE syndrome. Children with CHARGE syndrome require intensive medical management as well as numerous surgical interventions. They also need multidisciplinary follow up. Some of the hidden issues of CHARGE syndrome are often forgotten, one being the feeding adaptation of these children, which needs an early aggressive approach from a feeding team. As the child develops, challenging behaviors become more common and require adaptation of educational and therapeutic services, including behavioral and pharmacological interventions.
Topics: Abnormalities, Multiple; Choanal Atresia; Coloboma; DNA Helicases; DNA-Binding Proteins; Face; Genitalia; Heart Defects, Congenital; Humans; Mutation; Syndrome
PubMed: 16959034
DOI: 10.1186/1750-1172-1-34 -
Pediatrics and Neonatology Apr 2017With the growing understanding of the magnitude of genetic diseases in newborns and equally rapid advancement of tools used for genetic diagnoses, healthcare providers... (Review)
Review
With the growing understanding of the magnitude of genetic diseases in newborns and equally rapid advancement of tools used for genetic diagnoses, healthcare providers must have a sufficient knowledge base to both recognize and evaluate genetic diseases in the neonatal period. Genetic assessment has become an essential aspect of medicine, and professionals need to know when genetic evaluation is indispensable. Much progress has been made in recent years in utilizing massively parallel sequencing for rapid diagnosis of genetic conditions in neonates. Next-generation sequencing is increasingly being used for noninvasive prenatal diagnosis, and it may become an essential component of newborn screening. This review will define some basic genetic terms and concepts, explain the gamut of genetic testing available for early diagnosis of genetic diseases, and describe some common chromosomal abnormalities, genomic disorders, and single-gene diseases relevant to neonatal medicine.
Topics: Chromosome Aberrations; Congenital Abnormalities; Early Diagnosis; Genetic Testing; Humans; Infant, Newborn; Microarray Analysis; Mitochondrial Diseases; Neonatal Screening; Neonatology; Sequence Analysis
PubMed: 28277305
DOI: 10.1016/j.pedneo.2016.07.002 -
The Journal of Histochemistry and... Dec 2012Proteoglycans comprise a core protein to which one or more glycosaminoglycan chains are covalently attached. Although a small number of proteins have the capacity to be... (Review)
Review
Proteoglycans comprise a core protein to which one or more glycosaminoglycan chains are covalently attached. Although a small number of proteins have the capacity to be glycanated and become proteoglycans, it is now realized that these macromolecules have a range of functions, dependent on type and in vivo location, and have important roles in invertebrate and vertebrate development, maintenance, and tissue repair. Many biologically potent small proteins can bind glycosaminoglycan chains as a key part of their function in the extracellular matrix, at the cell surface, and also in some intracellular locations. Therefore, the participation of proteoglycans in disease is receiving increased attention. In this short review, proteoglycan structure, function, and localizations are summarized, with reference to accompanying reviews in this issue as well as other recent literature. Included are some remarks on proteoglycan and glycosaminoglycan localization techniques, with reference to the special physicochemical properties of these complex molecules.
Topics: Animals; Congenital Abnormalities; Diabetes Mellitus; Embryonic Development; Fibrosis; Glycosaminoglycans; Humans; Mutation; Neoplasms; Organ Specificity; Proteoglycans
PubMed: 23019015
DOI: 10.1369/0022155412464638 -
Molecular Genetics and Metabolism Jan 2014The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes.... (Review)
Review
The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. These processes range from a central role in anterior-posterior patterning of the developing embryo to roles in oncogenesis that are yet to be fully elucidated. In vertebrates there are a total of 39 Hox genes divided into 4 separate clusters. Of these, mutations in 10 Hox genes have been found to cause human disorders with significant variation in their inheritance patterns, penetrance, expressivity and mechanism of pathogenesis. This review aims to describe the various phenotypes caused by germline mutation in these 10 Hox genes that cause a human phenotype, with specific emphasis paid to the genotypic and phenotypic differences between allelic disorders. As clinical whole exome and genome sequencing is increasingly utilized in the future, we predict that additional Hox gene mutations will likely be identified to cause distinct human phenotypes. As the known human phenotypes closely resemble gene-specific murine models, we also review the homozygous loss-of-function mouse phenotypes for the 29 Hox genes without a known human disease. This review will aid clinicians in identifying and caring for patients affected with a known Hox gene disorder and help recognize the potential for novel mutations in patients with phenotypes informed by mouse knockout studies.
Topics: Animals; Congenital Abnormalities; Disease Models, Animal; Exome; Genes, Homeobox; Genetic Diseases, Inborn; Genetic Variation; Genome, Human; Genotype; Germ-Line Mutation; Humans; Mice; Molecular Biology; Multigene Family; Penetrance; Phenotype; Syndrome; Vertebrates
PubMed: 24239177
DOI: 10.1016/j.ymgme.2013.10.012 -
Clinics in Perinatology Jun 2015In the perinatal setting, chromosome imbalances cause a range of clinically significant disorders and increase the risk for other particular phenotypes. As technologies... (Review)
Review
In the perinatal setting, chromosome imbalances cause a range of clinically significant disorders and increase the risk for other particular phenotypes. As technologies have improved to detect increasingly smaller deletions and duplications, collectively referred to as copy number variants (CNVs), clinicians are learning the significant role that these types of genomic variants play in human disease and their high frequency in ∼ 1% of all pregnancies. This article highlights key aspects of CNV detection and interpretation used during the course of clinical care in the prenatal and neonatal periods. Early diagnosis and accurate interpretation are important for targeted clinical management.
Topics: Aneuploidy; Congenital Abnormalities; DNA Copy Number Variations; Genetic Testing; Genome, Human; Humans; Infant, Newborn
PubMed: 26042902
DOI: 10.1016/j.clp.2015.03.001