ABSTRACT
Congenital malformations (CMs) are permanent changes produced by abnormality of development in a body structure during prenatal life. Population based studies place the incidence of major malformations at about 2-3% of all live births. The etiology is mostly due multifactorial inheritance or unknown (50-80%). The continuum and gradual shift from genetics to genomics will offer new possibilities for diagnosis, treatment, prediction and prevention of congenital malformations. Genomics has many tools including pathogenomics, pharmacogenomics, nutrigenomics and bioinformatics. Pathogenomics will help to discover new genes or susceptibility genes and genetic variants with a role in the pathogenesis of CMs. Pharmacogenomics will identify genetic variants affecting the response to drugs and it should be applied to study drug induced birth defects. Nutrigenomics will determine the impact of diet on genome stability and how genotype determines nutritional requirements. Bioinformatics then will collect, store obtained data, which will facilitate analysis of systems biology questions involving relationships between genes, their variants and biological functions. This knowledge should be translated into more sensitive and specific genetic tests.
Subject(s)
Congenital Abnormalities/genetics , Congenital Abnormalities/prevention & control , Genomics/trends , Pharmacogenetics/trends , Humans , Nutrigenomics/trends , Risk FactorsABSTRACT
EEC syndrome an autosomal dominant disorder with variable expression and cardinal signs of ectrodactyly, ectodermal dysplasia, and orofacial clefts. In this report, we describe a patient with EEC syndrome, adipsic hypernatremia without brain anomalies, and bilateral renal stones, two manifestations that were not reported before.
Subject(s)
Abnormalities, Multiple , Cleft Lip , Cleft Palate , Ectodermal Dysplasia , Hypernatremia , Humans , Infant , Kidney Calculi , Male , SyndromeABSTRACT
Autosomal recessive congenital ichthyosis (ARCI) is a rare heterogeneous keratinization disorder of the skin. It is clinically divided into 2 subtypes, lamellar ichthyosis (LI) and congenital ichthyosiformis erythroderma (CIE). We investigated forty-three ARCI Egyptian individuals in 16 severe LI, and 10 CIE families. We identified 5 alleles in two Egyptian families as having intron-5/exon-6 splice acceptor mutation recognized by the MspI restriction endonuclease. This promoted to a frequency of 9.6% for this mutation (5 splice-mutation alleles/52 alleles tested). We extended our previous dataset to update the detection of R142H mutation in 4 CIE Egyptian families and one LI phenotype (frequency of 28.8%; 15/52), whereas we still had no R141H among our Egyptian population. There was no correlation between phenotype and genotype in our study. Surprisingly, the mutant alleles detected in intron-5 acceptor splice-site were associated with the other extreme of CIE phenotypes rather than the severe LI form. We clearly demonstrated that the ARCI Egyptian families in Upper Egypt was ethnically pure and had a tendency not to be a hybrid with other populations in Lower Egypt, Delta zone and Cairo city.
Subject(s)
Ichthyosiform Erythroderma, Congenital/genetics , Ichthyosis, Lamellar/genetics , Mutation , Transglutaminases/genetics , Adolescent , Adult , Age of Onset , Alleles , Alternative Splicing , Child , Child, Preschool , DNA Mutational Analysis , Deoxyribonuclease HpaII/metabolism , Egypt , Exons , Family Health , Female , Genes, Recessive , Genotype , Humans , Ichthyosiform Erythroderma, Congenital/diagnosis , Ichthyosis, Lamellar/diagnosis , Infant , Infant, Newborn , Introns , Male , Pedigree , Phenotype , Polymerase Chain ReactionABSTRACT
Phenylketonuria (PKU) is an autosomal recessive genetic disorder caused by defects in the phenylalanine hydroxylase (PAH) system. Our work aimed to screen the PAH locus for the presence of potentially useful short tandem repeats (STR) as markers for carrier detection in PKU families in Egypt, and to determine the level of PAH heterozygosity within the Egyptian population. The system contains at least eight independent alleles in the Egyptian population, transmitted in a Mendelian fashion. Variations in the number of STR in the 16 families studied gave rise to polymorphisms that proved to be suitable markers for PKU carrier detection and prenatal diagnosis. The most frequent allelic fragment size in PKU patients was 246 bp (35.7%), which together with a fragment of 254 bp accounted for 60.7% of the mutant chromosomes.
Subject(s)
Genetic Carrier Screening/methods , Genetic Testing/methods , Microsatellite Repeats/genetics , Phenylalanine Hydroxylase/genetics , Phenylketonurias , Polymorphism, Genetic/genetics , Asian People/genetics , Case-Control Studies , Egypt/epidemiology , Gene Frequency/genetics , Genetic Markers/genetics , Genetic Variation/genetics , Humans , Mutation/genetics , Pedigree , Phenylketonurias/diagnosis , Phenylketonurias/epidemiology , Phenylketonurias/genetics , Prenatal Diagnosis/methods , Time Factors , White People/geneticsABSTRACT
Phenylketonuria [PKU] is an autosomal recessive genetic disorder caused by defects in the phenylalanine hydroxylase [PAH] system. Our work aimed to screen the PAH locus for the presence of potentially useful short tandem repeats [STR] as markers for carrier detection in PKU families in Egypt, and to determine the level of PAH heterozygosity within the Egyptian population. The system contains at least eight independent alleles in the Egyptian population, transmitted in a Mendelian fashion. Variations in the number of STR in the 16 families studied gave rise to polymorphisms that proved to be suitable markers for PKU carrier detection and prenatal diagnosis. The most frequent allelic fragment size in PKU patients was 246 bp [35.7%], which together with a fragment of 254 bp accounted for 60.7% of the mutant chromosomes
Subject(s)
Asian People , Case-Control Studies , White People , Gene Frequency , Genetic Testing , Genetic Carrier Screening , Microsatellite Repeats , Mutation , Pedigree , Phenylketonurias , Polymorphism, Genetic , Phenylalanine HydroxylaseABSTRACT
Balhimycin, a vancomycin-type antibiotic from Amycolatopsis mediterranei, contains the unusual amino acid (S)-3,5-dihydroxyphenylglycine (Dpg), with an acetate-derived carbon backbone. After sequence analysis of the biosynthetic gene cluster, one gene, dpgA, for a predicted polyketide synthase (PKS) was identified, sharing 20-30% identity with plant chalcone synthases. Inactivation of dpgA resulted in loss of balhimycin production, and restoration was achieved by supplementation with 3,5-dihydroxyphenylacetic acid, which is both a possible product of a PKS reaction and a likely precursor of Dpg. Enzyme assays with the protein expressed in Streptomyces lividans showed that this PKS uses only malonyl-CoA as substrate to synthesize 3,5-dihydroxyphenylacetic acid. The PKS gene is organized in an operon-like structure with three downstream genes that are similar to enoyl-CoA-hydratase genes and a dehydrogenase gene. The heterologous co-expression of all four genes led to accumulation of 3,5-dihydroxyphenylglyoxylic acid. Therefore, we now propose a reaction sequence. The final step in the pathway to Dpg is a transamination. A predicted transaminase gene was inactivated, resulting in abolished antibiotic production and accumulation of 3,5-dihydroxyphenylglyoxylic acid. Interestingly, restoration was only possible by simultaneous supplementation with (S)-3,5-dihydroxyphenylglycine and (S)-4-hydroxyphenylglycine, indicating that the transaminase is essential for the formation of both amino acids.
Subject(s)
Bacterial Proteins , Coenzyme A Ligases/chemistry , Coenzyme A Ligases/genetics , Excitatory Amino Acid Antagonists/chemistry , Glycine/biosynthesis , Glycine/chemistry , Multienzyme Complexes/chemistry , Multienzyme Complexes/metabolism , Resorcinols/chemistry , Vancomycin/analogs & derivatives , Amino Acids/biosynthesis , Chromatography, High Pressure Liquid , Coenzyme A Ligases/biosynthesis , Gene Deletion , Glycine/analogs & derivatives , Glycopeptides/biosynthesis , Models, Chemical , Models, Genetic , Molecular Sequence Data , Mutagenesis, Site-Directed , Plasmids/metabolism , Sequence Analysis, DNA , Streptomyces/enzymology , Vancomycin/biosynthesisABSTRACT
This study was conducted on 500 full-term neonates and 25 older patients with congenital hypothyroidism (CH), newly or previously diagnosed. Alphafetoprotein (AFP) was elevated in two neonates. In one, persistent elevation of AFP and thyroid stimulating hormone (TSH) with low thyroxine (T4) were found (congenital hypothyroidism). In the other, AFP, TSH and T4 levels normalized (transient hypothyroidism). The mean AFP level in new CH patients was significantly higher than in previously diagnosed patients, and was higher in CH patients than in controls. Significant relationships were found between AFP and T4, AFP and TSH, and AFP and age. AFP is a sensitive indicator of thyroid status and can be used as a screening test for hypothyroidism from the first day of life and in follow-up of CH patients.
Subject(s)
Congenital Hypothyroidism , Hypothyroidism/diagnosis , Neonatal Screening/methods , alpha-Fetoproteins/metabolism , Adolescent , Adult , Age Factors , Bilirubin/blood , Case-Control Studies , Child , Child, Preschool , Creatinine/blood , Female , Humans , Hypothyroidism/blood , Infant , Infant, Newborn , Male , Neonatal Screening/standards , Sensitivity and Specificity , Thyroid Function Tests , Thyrotropin/blood , Thyroxine/bloodABSTRACT
This study was carried out with 33 spinal muscular atrophy (SMA) patients. DNA molecular studies of the SMA gene on the long arm of chromosome 5 (5q11.2q13.3) revealed homozygous deletion of exon 7 in 55% of cases, 36% of whom also had a homozygous delition of exon 8. The adult patients were heterozygous for an abnormal size exon 8. The remaining patients had either compound heterozygote deletion of exons 7 and 8 or were normal for both. There may therefore be 5q-unlinked SMA or SMA due to other mutations. Detection of deletions of SMA exons 7 and 8 is a powerful diagnostic test in patients with SMA, but other mutations among Egyptians must also be sought.
Subject(s)
Chromosomes, Human, Pair 5/genetics , DNA Mutational Analysis/methods , Gene Deletion , Muscular Atrophy, Spinal/diagnosis , Muscular Atrophy, Spinal/genetics , Adult , Age of Onset , Case-Control Studies , Child , Child, Preschool , Consanguinity , Disease Progression , Egypt/epidemiology , Female , Genetic Testing , Genotype , Heterozygote , Homozygote , Humans , Infant , Male , Muscular Atrophy, Spinal/classification , Muscular Atrophy, Spinal/epidemiology , Phenotype , Severity of Illness IndexABSTRACT
Cardiac and ocular manifestations were evaluated in 21 patients clinically suspected of mucopolysaccharidosis. After electrophoresis analysis of urinary glycoaminoglycans, 3 patients were excluded because their results did not correlate with any known type of mucopolysaccharidosis. Echocardiography revealed abnormal findings in 11 patients (61.1%). The mitral valve was the most commonly affected valve; 7 patients (38.9%) had thickened mitral valve and 6 had mitral regurge. Corneal opacities were found in 3 patients (16.7%) and progressive increase in intraocular pressure in 1 patient (5.6%), while fundus examination showed early optic atrophy in 1 patient (5.6%) and bilateral papilloedema in 2 patients (11.1%).
Subject(s)
Corneal Opacity/etiology , Mitral Valve Insufficiency/etiology , Mitral Valve Stenosis/etiology , Mucopolysaccharidoses/complications , Ocular Hypertension/etiology , Optic Atrophy/etiology , Papilledema/etiology , Adolescent , Case-Control Studies , Child , Child, Preschool , Coloring Agents , Corneal Opacity/diagnosis , Corneal Opacity/epidemiology , Creatinine/urine , Echocardiography, Doppler, Color , Egypt/epidemiology , Electrophoresis/methods , Electrophoresis/standards , Female , Glycosaminoglycans/urine , Humans , Male , Mitral Valve Insufficiency/diagnostic imaging , Mitral Valve Insufficiency/epidemiology , Mitral Valve Stenosis/diagnostic imaging , Mitral Valve Stenosis/epidemiology , Mucopolysaccharidoses/diagnosis , Mucopolysaccharidoses/urine , Ocular Hypertension/diagnosis , Ocular Hypertension/epidemiology , Ophthalmoscopy , Optic Atrophy/diagnosis , Optic Atrophy/epidemiology , Papilledema/diagnosis , Papilledema/epidemiology , Tolonium ChlorideABSTRACT
Cardiac and ocular manifestations were evaluated in 21 patients clinically suspected of mucopolysaccharidosis. After electrophoresis analysis of urinary glycoaminoglycans, 3 patients were excluded because their results did not correlate with any known type of mucopolysaccharidosis. Echocardiography revealed abnormal findings in 11 patients [61.1%]. The mitral valve was the most commonly affected valve; 7 patients [38.9%] had thickened mitral valve and 6 had mitral regurge. Corneal opacities were found in 3 patients [16.7%] and progressive increase in intraocular pressure in 1 patient [5.6%], while fundus examination showed early optic atrophy in 1 patient [5.6%] and bilateral papilloedema in 2 patients [11.1%]
Subject(s)
Case-Control Studies , Child, Preschool , Coloring Agents , Corneal Opacity , Echocardiography, Doppler, Color , Electrophoresis , Mitral Valve Insufficiency , Mitral Valve Stenosis , Ocular Hypertension , Optic Atrophy , Papilledema , MucopolysaccharidosesABSTRACT
This study was carried out with 33 spinal muscular atrophy [SMA] patients. DNA molecular studies of the SMA gene on the long arm of chromosome 5 [5q11.2q13.3] revealed homozygous deletion of exon 7 in 55% of cases, 36% of whom also had a homozygous delition of exon 8. The adult patients were heterozygous for an abnormal size exon 8. The remaining patients had either compound heterozygote deletion of exons 7 and 8 or were normal for both. There may therefore be 5q-unlinked SMA or SMA due to other mutations. Detection of deletions of SMA exons 7 and 8 is a powerful diagnostic test in patients with SMA, but other mutations among Egyptians must also be sought
Subject(s)
Age of Onset , Case-Control Studies , Chromosomes, Human, Pair 5 , DNA Mutational Analysis , Disease Progression , Gene Deletion , Heterozygote , Homozygote , Phenotype , Muscular Atrophy, SpinalABSTRACT
This study was conducted on 500 full-term neonates and 25 older patients with congenital hypothyroidism [CH], newly or previously diagnosed. Alphafetoprotein [AFP] was elevated in two neonates. In one, persistent elevation of AFP and thyroid stimulating hormone [TSH] with low thyroxine [T4] were found [congenital hypothyroidism]. In the other, AFP, TSH and T4 levels normalized [transient hypothyroidism]. The mean AFP level in new CH patients was significantly higher than in previously diagnosed patients, and was higher in CH patients than in controls. Significant relationships were found between AFP and T4, AFP and TSH, and AFP and age. AFP is a sensitive indicator of thyroid status and can be used as a screening test for hypothyroidism from the first day of life and in follow-up of CH patients
