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Journal of Human Genetics Aug 2017Mutations inTFAP2B has been reported in patients with isolated patent ductus arteriosus (PDA) and Char syndrome. We performed mutation analysis of TFAP2B in 43 patients...
Mutations inTFAP2B has been reported in patients with isolated patent ductus arteriosus (PDA) and Char syndrome. We performed mutation analysis of TFAP2B in 43 patients with isolated PDA, 7 patients with PDA with other congenital heart defects and 286 patients with isolated tooth agenesis with or without other dental anomalies. The heterozygous c.1006G>A mutation was identified in 20 individuals. Those mutation carriers consisted of 1 patient with term PDA (1/43), 16 patients with isolated tooth agenesis with or without other dental anomalies (16/286; 5.6%), 1 patient with PDA and severe valvular aortic stenosis and tooth agenesis (1/4) and 2 normal controls (2/100; 1%). The mutation is predicted to cause an amino-acid substitution p.Val336Ile in the TFAP2B protein. Tfap2b expression during early mouse tooth development supports the association of TFAP2B mutation and dental anomalies. It is hypothesized that this incidence might have been the result of founder effect. Here we report for the first time that TFAP2B mutation is associated with tooth agenesis, microdontia, supernumerary tooth and root maldevelopment. In addition, we also found that TFAP2B mutations, the common causes of PDA in Caucasian, are not the common cause of PDA in Thai population.
Topics: Abnormalities, Multiple; Adolescent; Adult; Child, Preschool; DNA Mutational Analysis; Ductus Arteriosus, Patent; Face; Female; Fingers; Heart Defects, Congenital; Humans; Incidence; Male; Mutation; Pedigree; Thailand; Tooth Abnormalities; Transcription Factor AP-2; Young Adult
PubMed: 28381879
DOI: 10.1038/jhg.2017.37 -
Biochemical Society Transactions Jun 2021The Eyes Absent (EYA) transactivator-phosphatase proteins are important contributors to cell-fate determination processes and to the development of multiple organs. The... (Review)
Review
The Eyes Absent (EYA) transactivator-phosphatase proteins are important contributors to cell-fate determination processes and to the development of multiple organs. The transcriptional regulatory activity as well as the protein tyrosine phosphatase activities of the EYA proteins can independently contribute to proliferation, differentiation, morphogenesis and tissue homeostasis in different contexts. Aberrant EYA levels or activity are associated with numerous syndromic and non-syndromic developmental disorders, as well as cancers. Commensurate with the multiplicity of biochemical activities carried out by the EYA proteins, they impact upon a range of cellular signaling pathways. Here, we provide a broad overview of the roles played by EYA proteins in development, and highlight the molecular signaling pathways known to be linked with EYA-associated organ development and developmental disorders.
Topics: Animals; Congenital Abnormalities; Eye; Gene Expression Regulation, Developmental; Genetic Predisposition to Disease; Humans; Kidney; Mutation; Protein Tyrosine Phosphatases; Trans-Activators
PubMed: 34196366
DOI: 10.1042/BST20201302 -
Journal of Paediatrics and Child Health Feb 2018
Topics: Child, Preschool; Chromosomes, Human, Pair 9; Congenital Abnormalities; Female; Humans; Parent-Child Relations; Parents; Translocation, Genetic; Trisomy
PubMed: 29417675
DOI: 10.1111/jpc.13840 -
European Journal of Medical Genetics Mar 2021Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome is a sex development disorder that affects 1 in every 4500 46, XX live births. At least a subset of MRKH syndrome is... (Review)
Review
Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome is a sex development disorder that affects 1 in every 4500 46, XX live births. At least a subset of MRKH syndrome is genetically related to which various candidate genes have been identified. The growth regulation by estrogen in breast cancer 1-like gene (GREB1L) is an androgen-regulated gene reported to be a co-activator of the retinoic acid receptor gene (RAR). Thus expression levels of GREB1L have implications on renal system cellular differentiation, morphogenesis, and homeostasis in vertebrates. Variants of GREB1L have been reported in familial and sporadic MRKH Syndrome and more importantly, in a three-generation family ofMRKH syndrome propositae. Much the same way, Mutants of GREB1L have also been identified in isolated bilateral renal agenesis and deafness both of which are extra-genital tract anomalies in MRKH type 2. Again, renal agenesis transgenic mice have been produced from an E13.5 CRISPR/cas9 GREB1L mutagenesis. Though no GREB1L mutation has been reported in cardiac malformation, there is evidence that GREB1L is involved in ventricular development. Here, we intorigate evidence that projects GREB1L as a candidate gene of Mayer-Rokitansky-Küster-Hauser Syndrome and propose that functional validation analysis to that effect is imparative.
Topics: 46, XX Disorders of Sex Development; Animals; Congenital Abnormalities; Humans; Mullerian Ducts; Mutation; Neoplasm Proteins; Phenotype
PubMed: 33548512
DOI: 10.1016/j.ejmg.2021.104158 -
Circulation Journal : Official Journal... Apr 2017Twenty years ago, chromosomal abnormalities were the only identifiable genetic causes of a small fraction of congenital heart defects (CHD). Today, a de novo or... (Review)
Review
Twenty years ago, chromosomal abnormalities were the only identifiable genetic causes of a small fraction of congenital heart defects (CHD). Today, a de novo or inherited genetic abnormality can be identified as pathogenic in one-third of cases. We refer to them here as monogenic causes, insofar as the genetic abnormality has a readily detectable, large effect. What explains the other two-thirds? This review considers a complex genetic basis. That is, a combination of genetic mutations or variants that individually may have little or no detectable effect contribute to the pathogenesis of a heart defect. Genes in the embryo that act directly in cardiac developmental pathways have received the most attention, but genes in the mother that establish the gestational milieu via pathways related to metabolism and aging also have an effect. A growing body of evidence highlights the pathogenic significance of genetic interactions in the embryo and maternal effects that have a genetic basis. The investigation of CHD as guided by a complex genetic model could help estimate risk more precisely and logically lead to a means of prevention.
Topics: Genetic Variation; Heart; Heart Defects, Congenital; Humans; Mutation
PubMed: 28381817
DOI: 10.1253/circj.CJ-16-1343 -
Cells, Tissues, Organs 2018The function of normal and defective candidate genes for human genetic diseases, which are rapidly being identified in large numbers by human geneticists and the... (Review)
Review
The function of normal and defective candidate genes for human genetic diseases, which are rapidly being identified in large numbers by human geneticists and the biomedical community at large, will be best studied in relevant and predictive model organisms that allow high-speed verification, analysis of underlying developmental, cellular and molecular mechanisms, and establishment of disease models to test therapeutic options. We describe and discuss the pros and cons of the frog Xenopus, which has been extensively used to uncover developmental mechanisms in the past, but which is being underutilized as a biomedical model. We argue that Xenopus complements the more commonly used mouse and zebrafish as a time- and cost-efficient animal model to study human disease alleles and mechanisms.
Topics: Alleles; Animals; Ciliary Motility Disorders; Ciliopathies; Congenital Abnormalities; Disease Models, Animal; Genetic Diseases, Inborn; Heart Defects, Congenital; Humans; Mutation; Xenopus laevis
PubMed: 30092565
DOI: 10.1159/000490898 -
Seminars in Perinatology Feb 2016Patients and providers are faced with a wide array of choices to screen for structural abnormalities, aneuploidy, and genetic diseases in the prenatal period. It is... (Review)
Review
Patients and providers are faced with a wide array of choices to screen for structural abnormalities, aneuploidy, and genetic diseases in the prenatal period. It is important to consider the features of the diseases being screened for, the characteristics of the screening tests used, and the population being screened when evaluating prenatal screening techniques.
Topics: Amniocentesis; Aneuploidy; Chorionic Villi Sampling; Chromosome Disorders; Congenital Abnormalities; DNA; Female; Fetus; Genetic Testing; Humans; Pregnancy; Prenatal Diagnosis; Ultrasonography, Prenatal
PubMed: 26708051
DOI: 10.1053/j.semperi.2015.11.002 -
Clinical Genetics Mar 2017Congenital heart disease (CHD), one of the causes of childhood morbidity and mortality, is mainly triggered by a combination of environmental and genetic factors.... (Review)
Review
Congenital heart disease (CHD), one of the causes of childhood morbidity and mortality, is mainly triggered by a combination of environmental and genetic factors. Several susceptible genes, such as NKX2-5, GATA4 and TBX5, have been reported as closely related to heart and vessel development. CHD subtypes are classified into diverse clinical phenotypes, such as atrial septal defects (ASD), ventricular septal defects (VSD), tetralogy of Fallot (TOF), and Holt-Oram syndrome (HOS). Here, we summarize the associations of the genetic variants in these three genes with CHD subtypes. CHD-associated variants of NKX2-5 locate mainly in the tinman domain and the homeodomain. Mutations in the homeodomain are correlated with ASD and atrioventricular (AV) block subtypes. VSD-associated variants of GATA4 are mainly at its terminal ends. Variants of TBX5 gene are primarily in exons 3, 4, 5 and 7 and highly associated with HOS subtype. Hence, the variant distribution of NKX2-5, GATA4 and TBX5 are tightly associated with particular CHD subtypes. Further structure-modelling analysis revealed that these mutated amino acid residuals maintain their DNA-binding ability and structural stability. Therefore structural features of these genes may be used to predict the high risk of CHD subtypes in infants.
Topics: Abnormalities, Multiple; GATA4 Transcription Factor; Genetic Association Studies; Genetic Predisposition to Disease; Heart Defects, Congenital; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Homeobox Protein Nkx-2.5; Humans; Lower Extremity Deformities, Congenital; Mutation; Phenotype; T-Box Domain Proteins; Tetralogy of Fallot; Upper Extremity Deformities, Congenital
PubMed: 27426723
DOI: 10.1111/cge.12835 -
BMC Medical Genomics Oct 2023Whole-exome sequencing (WES) significantly improves the diagnosis of the etiology of fetal structural anomalies. This study aims to evaluate the diagnostic value of...
BACKGROUND
Whole-exome sequencing (WES) significantly improves the diagnosis of the etiology of fetal structural anomalies. This study aims to evaluate the diagnostic value of prenatal WES and to investigate the pathogenic variants in structurally abnormal fetuses.
METHODS
We recruited 144 fetuses with structural anomalies between 14 and 2020 and 15 December 2021 in the study. Genetic screening was performed by WES combined with karyotyping and chromosomal microarray analysis. The molecular diagnostic yield of prenatal WES for each type of fetal structural anomaly and the identified pathogenic genes and mutations were reported.
RESULTS
In this study, we retrospectively analyzed the clinical and genetic data of 145 structurally anomalous fetuses. These cases were classified into 9 phenotypic classes based on antenatal ultrasound findings. Thirty-eight pathogenic variants in 24 genes were identified in 35 of the 145 cases, including 14 novel variants in 13 genes (EP300, MYH3, TSC2, MMP9, CPLANE1, INVS, COL1A1, EYA1, TTC21B, MKS1, COL11A2, PDHA1 and L1CAM). Five additional pathogenic variants were classified as incidental findings. Our study showed that the overall diagnosis rate of WES was 28.1% (27/96) in the parent-fetus trio cases and 16.3% (8/49) in the proband-only cases. Fetuses with musculoskeletal anomalies had the highest diagnostic yield (51.4%, 19/37). In addition, FGFR3 and COL1A1 were the most common pathogenic genes.
CONCLUSIONS
Our work expands the mutation spectrum of the genes associated with fetal structural anomalies and provides valuable information for future parental genetic counselling and pregnancy management of the structurally anomalous fetuses.
Topics: Female; Humans; Pregnancy; East Asian People; Exome Sequencing; Fetus; Pregnancy Trimester, First; Prenatal Diagnosis; Retrospective Studies; Ultrasonography, Prenatal; Congenital Abnormalities
PubMed: 37880672
DOI: 10.1186/s12920-023-01697-3 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... May 2018Congenital heart disease (CHD) is a type of birth defects due to the abnormal development of heart and blood vessels during embryonic stage. Studies indicate that the... (Review)
Review
Congenital heart disease (CHD) is a type of birth defects due to the abnormal development of heart and blood vessels during embryonic stage. Studies indicate that the etiology of CHD is complicated. Genetic and epigenetic mechanisms including chromosomal abnormalities, gene mutations, nucleic acid modifications, non-coding RNAs may play important roles in CHD. At present, genetic mechanisms such as chromosome abnormality and gene mutation have been widely used in the diagnosis and treatment of clinical diseases. However, the application of genetic and epigenetic modification in diagnosis and treatment of CHD still need further research. This paper reviews the relationship between chromosomal abnormality, gene mutation, copy number variation, epigenetic modification and the occurrence of CHD, which may provide a basis for further exploring the early diagnosis and individualized therapy of CHD.
Topics: Chromosome Aberrations; DNA Copy Number Variations; Epigenesis, Genetic; Heart Defects, Congenital; Humans; Mutation
PubMed: 30226321
DOI: 10.3785/j.issn.1008-9292.2018.06.02