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American Journal of Medical Genetics.... Nov 2009Joubert syndrome (JBTS; OMIM 213300) is a rare, autosomal recessive disorder characterized by a specific congenital malformation of the hindbrain and a broad spectrum of... (Review)
Review
Joubert syndrome (JBTS; OMIM 213300) is a rare, autosomal recessive disorder characterized by a specific congenital malformation of the hindbrain and a broad spectrum of other phenotypic findings that is now known to be caused by defects in the structure and/or function of the primary cilium. The complex hindbrain malformation that is characteristic of JBTS can be identified on axial magnetic resonance imaging and is known as the molar tooth sign (MTS); other diagnostic criteria include intellectual disability, hypotonia, and often, abnormal respiratory pattern and/or abnormal eye movements. In addition, a broad spectrum of other anomalies characterize Joubert syndrome and related disorders (JSRD), and may include retinal dystrophy, ocular coloboma, oral frenulae and tongue tumors, polydactyly, cystic renal disease (including cystic dysplasia or juvenile nephronophthisis), and congenital hepatic fibrosis. The clinical course can be variable, but most children with this condition survive infancy to reach adulthood. At least eight genes cause JSRD, with some genotype-phenotype correlations emerging, including the association between mutations in the MKS3 gene and hepatic fibrosis characteristic of the JSRD subtype known as COACH syndrome. Several of the causative genes for JSRD are implicated in other ciliary disorders, such as juvenile nephronophthisis and Meckel syndrome, illustrating the close association between these conditions and their overlapping clinical features that reflect a shared etiology involving the primary cilium.
Topics: Abnormalities, Multiple; Adolescent; Brain; Child; Child, Preschool; Cilia; Ciliary Motility Disorders; Congenital Abnormalities; Developmental Disabilities; Female; Genes, Recessive; Genotype; Humans; Infant; Male; Pregnancy; Prenatal Diagnosis; Syndrome
PubMed: 19876931
DOI: 10.1002/ajmg.c.30229 -
Journal of Clinical Pathology Nov 1972
Topics: Amniocentesis; Chromosome Aberrations; Chromosome Disorders; Congenital Abnormalities; Down Syndrome; Female; Humans; Lesch-Nyhan Syndrome; Pregnancy; Prenatal Diagnosis
PubMed: 4265194
DOI: 10.1136/jcp.25.11.1008-c -
British Medical Journal Feb 1972
Topics: Chromosome Aberrations; Chromosome Disorders; Congenital Abnormalities; Counseling; Eugenics; Genetic Diseases, Inborn; Humans
PubMed: 5008048
DOI: No ID Found -
American Journal of Medical Genetics.... Mar 2020Congenital heart defect is one of the most common structural birth defects in the human population. It is highly associated with heterotaxy, a birth defect involving... (Review)
Review
Congenital heart defect is one of the most common structural birth defects in the human population. It is highly associated with heterotaxy, a birth defect involving randomized left-right patterning of visceral organ situs. Large scale mouse forward genetics have led to the finding of a central role for cilia in CHD pathogenesis, with some cilia and non-cilia mutations causing CHD with heterotaxy. Interestingly, many of the mutations causing CHD with heterotaxy can give rise to three laterality outcomes comprising normal situs solitus, mirror symmetric situs inversus totalis, or randomized situs with heterotaxy. Given CHD is largely observed only with heterotaxy, this suggests a new paradigm is needed for investigating the genetics of CHD associated with heterotaxy. Furthermore, analysis of data from multiple large birth cohorts have independently confirmed a broader involvement of laterality disturbance in CHD. This was demonstrated by the common cooccurrence of rare laterality defects with CHD lesions of a wide spectrum. These findings suggest left-right patterning is tightly intertwined with the developmental processes that regulate cardiac morphogenesis and its disturbance may contribute to all types of CHD even in the absence of laterality defects.
Topics: Animals; Body Patterning; Cilia; Congenital Abnormalities; Disease Models, Animal; Heart Defects, Congenital; Humans; Mice; Mutation
PubMed: 31999049
DOI: 10.1002/ajmg.c.31768 -
International Journal of Molecular... Jan 2017Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important... (Meta-Analysis)
Meta-Analysis Review
Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype-phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations-a frequent problem in orphan diseases-we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype-phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.
Topics: Blood Coagulation Disorders, Inherited; Carbon-Carbon Ligases; Congenital Abnormalities; Eye; Gene Knockout Techniques; Genetic Association Studies; Genetic Counseling; Genetic Predisposition to Disease; Genotype; Humans; Mutation; Phenotype; Polymorphism, Single Nucleotide; Protein Interaction Domains and Motifs; Skin; Vitamin K
PubMed: 28125048
DOI: 10.3390/ijms18020240 -
Epilepsia 2005To search for clues to molecular genetics of common idiopathic epilepsy syndromes. Genetic defects have been identified recently in certain inherited epilepsy syndromes... (Review)
Review
PURPOSE
To search for clues to molecular genetics of common idiopathic epilepsy syndromes. Genetic defects have been identified recently in certain inherited epilepsy syndromes in which the phenotypes are similar to those of common idiopathic epilepsies.
METHODS
Mutations identified as the causes of inherited idiopathic epilepsies were reviewed.
RESULTS
Mutations of the genes encoding two subunits of the neuronal nicotinic acetylcholine receptor were found in autosomal dominant nocturnal frontal lobe epilepsy. Mutations of two K(+)-channel genes were identified in benign familial neonatal convulsions. Mutations of the genes encoding several subunits of the voltage-gated Na(+)-channel and gamma-aminobutyric acid (GABA)(A) receptor also were identified as the underlying causes of various epilepsy syndromes, such as autosomal dominant epilepsy with febrile seizures plus, benign familial neonatal infantile seizures, and autosomal dominant juvenile myoclonic epilepsy. Mutations within the same gene may result in different epilepsy phenotypes. Thus, the Na(+) channel, GABA(A) receptor, and their auxiliaries may be involved in the pathogenesis of various types of epilepsy. Some forms of juvenile myoclonic epilepsy, idiopathic generalized epilepsy, and absence epilepsy may result from mutations of Ca(2+) channels. Mutations of the Cl(-) channel have been recently found to be associated with a certain type of epilepsy. The recent discovery that mutations of LGI1, a gene encoding a nonchannel molecule, are associated with autosomal partial epilepsy with auditory features may provide a new insight into our understanding of the genetics of idiopathic epilepsy.
CONCLUSIONS
These findings suggest the involvement of brain channelopathies in the pathogenesis of certain types of idiopathic epilepsy.
Topics: Codon, Nonsense; Congenital Abnormalities; Epilepsies, Partial; Epilepsy; Epilepsy, Benign Neonatal; Epilepsy, Frontal Lobe; Genes, Dominant; Humans; Ion Channels; Mutation; Pedigree; Phenotype; Seizures, Febrile; Syndrome
PubMed: 15816978
DOI: 10.1111/j.0013-9580.2005.461011.x -
British Heart Journal May 1970In isolated congenital heart disease genetic factors have been shown from family studies, individual pedigree analyses, the frequency of consanguinity, examination of... (Review)
Review
In isolated congenital heart disease genetic factors have been shown from family studies, individual pedigree analyses, the frequency of consanguinity, examination of data from twins, and possibly from cytogenetics. In defects of the atrial septum, where data are most complete, genetic factors appear to be important, particularly in secundum atrial septal defect. In the syndromes with abnormal chromosomes in which congenital heart disease is common, the cardiovascular abnormality is probably directly associated with the abnormal genetic material present. In hereditary disorders with normal chromosomes in which congenital heart disease features, the pattern of inheritance suggests transmission by a single gene or group of genes. The cardiovascular abnormality is genetically determined, though it may not become apparent until many years after birth.
Topics: Adult; Animals; Child; Child, Preschool; Chromosome Aberrations; Chromosome Disorders; Consanguinity; Diseases in Twins; Dogs; Down Syndrome; Family; Female; Genes; Genetics, Medical; Hand Deformities, Acquired; Heart Defects, Congenital; Heart Septal Defects, Atrial; Humans; Infant; Male; Mucopolysaccharidoses; Pedigree; Retinitis Pigmentosa; Tetralogy of Fallot; Thumb; Trisomy; Turner Syndrome
PubMed: 4246190
DOI: 10.1136/hrt.32.3.281 -
Journal of Medical Genetics Jun 2002Several autosomal dominantly inherited human syndromes have recently been shown to result from mutations in the p63 gene. These syndromes have various combinations of... (Review)
Review
Several autosomal dominantly inherited human syndromes have recently been shown to result from mutations in the p63 gene. These syndromes have various combinations of limb malformations fitting the split hand-split foot spectrum, orofacial clefting, and ectodermal dysplasia. The p63 syndrome family includes the EEC syndrome, AEC syndrome, ADULT syndrome, limb-mammary syndrome, and non-syndromic split hand/foot malformation. The pattern of heterozygous mutations is distinct for each of these syndromes. The functional effects on the p63 proteins also vary between syndromes. In all of these syndromes, the mutation appears to have both dominant negative and gain of function effects rather than causing a simple loss of function.
Topics: Congenital Abnormalities; DNA-Binding Proteins; Ectodermal Dysplasia; Foot Deformities, Congenital; Genes, Tumor Suppressor; Genotype; Hand Deformities, Congenital; Humans; Membrane Proteins; Mouth Abnormalities; Mutation; Phenotype; Phosphoproteins; Syndrome; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins
PubMed: 12070241
DOI: 10.1136/jmg.39.6.377 -
BMC Pediatrics Apr 2023White-Sutton syndrome is an autosomal dominant neurodevelopmental disorder caused by heterozygous mutation in POGZ (Pogo Transposable Element Derived with ZNF Domain).... (Review)
Review
BACKGROUND
White-Sutton syndrome is an autosomal dominant neurodevelopmental disorder caused by heterozygous mutation in POGZ (Pogo Transposable Element Derived with ZNF Domain). This syndrome is characterized by delayed psychomotor development apparent in infancy and abnormal facial features. To date, 80 cases have been reported in the literature; however, the phenotypic characterizations remain incomplete.
CASE PRESENTATION
We herein describe a 2-year-old girl harboring a novel frameshift de novo POGZ variant: c.2746del (p.Thr916ProfsTer12). This patient presented with multisystem abnormalities affecting the digestive tract and neurological functioning, as well as congenital heart disease, which involved an atrial septal defect (18 × 23 × 22 mm) with pulmonary arterial hypertension (42 mmHg). The relationship between congenital heart disease and White-Sutton syndrome as described in both the GeneReview and OMIM databases (#616,364) remains unclear. A review of the current literature revealed 18 cases of White-Sutton syndrome with POGZ variants and congenital heart disease, and we summarize their clinical features in this study.
CONCLUSIONS
Our findings based on the present case and those in the literature indicate a relationship between POGZ mutation and congenital heart disease.
Topics: Female; Humans; Child, Preschool; Heart Defects, Congenital; Intellectual Disability; Mutation; Frameshift Mutation; Abnormalities, Multiple; Phenotype
PubMed: 37016333
DOI: 10.1186/s12887-023-03972-9 -
Genetics and Molecular Research : GMR Oct 2013The runt-related transcription factor 2 gene (RUNX2), which is also known as CBFA1, is a master regulatory gene in bone formation. Mutations in RUNX2 have been...
The runt-related transcription factor 2 gene (RUNX2), which is also known as CBFA1, is a master regulatory gene in bone formation. Mutations in RUNX2 have been identified in cleidocranial dysplasia (CCD) patients. CCD is a rare autosomal dominant skeletal dysplasia that is characterized by delayed closure of cranial sutures, aplastic or hypoplastic clavicle formation, short stature, and dental anomalies, including malocclusion, supernumerary teeth, and delayed eruption of permanent teeth. In this study, we recruited three de novo CCD families and performed mutational analysis of the RUNX2 gene as a candidate gene approach. The mutational study revealed three disease-causing mutations: a missense mutation (c.674G>A, p.Arg225Gln), a frameshift mutation (c.1119delC, p.Arg374Glyfs*), and a nonsense mutation (c.1171C>T, p.Arg391*). Clinical examination revealed a unique dental phenotype (no typical supernumerary teeth, but duplication of anterior teeth) in one patient. We believe that this finding will broaden the understanding of the mechanism of supernumerary teeth formation and CCD-related phenotypes.
Topics: Adolescent; Base Sequence; Child; Cleidocranial Dysplasia; Codon, Nonsense; Core Binding Factor Alpha 1 Subunit; DNA Mutational Analysis; Female; Frameshift Mutation; Genetic Association Studies; Humans; Jaw; Male; Mutation, Missense; Radiography; Tooth Abnormalities
PubMed: 24222232
DOI: 10.4238/2013.October.15.5