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Results for “Microdeletion”

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At least 1,243 records · Page 69Linked to original sources
PubMed2004

Autosomal dominant B-cell immunodeficiency, distal limb anomalies and urogenital malformations (BILU syndrome) - report of a second family.

A family with an unusual combination of B-cell immunodeficiency, distal limb abnormalities, genitourinary malformations, and mild dysmorphic features has recently been described. Here, we report a second family with similar features, which also shows autosomal dominant inheritance. In affected individuals from both families, sequence analysis of candidate gene HOXA13 did not identify a mutation, and there was no evidence of a microdeletion involving either HOXA13 or the HOXA cluster as a whole. We further delineate the phenotype of this condition in females and add weight to the observation that this is a true syndromic association.

Adult↗
PubMed2006

Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a markedly elevated risk of schizophrenia in adulthood. Cognitive impairments such as a low IQ and deficits in attention and executive function are common in childhood. The catechol O-methyltransferase (COMT) gene maps within the deleted region and is involved in the degradation of dopamine, a neurotransmitter thought to be important in cognition and the development of schizophrenia. Thus, we examined the correlation between neurocognitive deficits and a common polymorphism Val(158)Met in the COMT gene in a cohort of children with 22q11DS. Our results show that children with 22q11DS who have the Met allele have higher IQ and achievement scores and perform better on measures of prefrontal cognition, such as the Continuous Performance Task, as compared with those with the Val allele. These results confirm that the hemizygous COMT Val(158)Met genotype impacts upon cognition in children with 22q11DS.

Adolescent↗
PubMed2006

TEM, FISH and molecular studies in infertile men with pericentric inversion of chromosome 9.

Pericentric inversions involving the secondary constriction (qh) region of chromosome 9 are considered to be normal variants of human karyotype. A number of investigators have suggested that chromosomal anomalies can contribute to human infertility causing spermatogenetic derangement. The present study was aimed at verifying the influence of chromosome 9 inversion on human spermatogenesis. Semen samples of 18 male carriers of chromosome 9 inversion, analysed by light microscopy, revealed that five patients were azoospermic. PCR analysis demonstrated that two of them also had Y microdeletions. The other 13 showed generally normal sperm concentrations and reduced motility. The morphological characteristics of sperm were studied by TEM and the data were elaborated by a mathematical formula. Sperm pathologies resulted more frequently in the studied group compared to controls, particularly apoptosis. Partial sequences of the A-kinase anchoring protein (Akap) 4 and 3 genes were performed in all patients, as a previous study by our group highlighted Dysplasia of Fibrous Sheath (DFS) defect in two men with inv 9 investigations. The possible effect of chromosome 9 inversion on meiotic chromosome segregation was investigated by FISH, which showed an increased incidence of diploidy. We hypothesized that this inversion could have variable effects on spermatogenesis, from azoospermia to severely altered sperm morphology, motility and meiotic segregation.

Adolescent↗
PubMed2004

The Van der Woude syndrome: a case report and review of the literature.

The Van der Woude syndrome is a rare autosomal dominant developmental malformation usually associated with bilateral lower lip pits. These congenital lip pits appear clinically as a malformation in the vermilion border of the lip, with or without excretion. As a genetic defect has been identified as a microdeletion of chromosome bands 1q32-q41, genetic counselling of patients may be considered. A nonsense mutation in the interferon regulatory factor-6 (IRF-6) is discussed as a pathogenic relevant factor. Therapeutic intervention is generally not necessary, although surgical excision is especially indicated in patients with recurrent inflammation. Physicians should be aware of the Van der Woude syndrome because it has been reported to be associated with a variety of malformations or other congenital disorders.

Adult↗
PubMed2005

Annotation: velo-cardio-facial syndrome.

BACKGROUND: Velo-cardio-facial syndrome (VCFS), the most frequent known interstitial deletion identified in man, is associated with chromosomal microdeletions in the q11 band of chromosome 22. Individuals with VCFS are reported to have a characteristic behavioural phenotype with high rates of behavioural, psychiatric, neuropsychological and linguistic disorders. METHODS: A selective literature review was undertaken. RESULTS: Children and adults with VCFS have high rates of behavioural, psychiatric and communication disorders. While VCFS children have high rates of ADHD, anxiety and affective disorders, adults have high rates of psychotic disorders, particularly schizophrenia. In addition, the presence of a chromosome 22q11 deletion is associated with specific neuropsychological and neuroanatomical abnormalities. CONCLUSIONS: People with VCFS have a characteristic behavioural phenotype with high rates of behavioural, psychiatric, neuropsychological and communication disorders. Early diagnosis and treatment within a multidisciplinary framework is of paramount importance for VCFS individuals as this will have a major effect in determining the long-term outcome in affected individuals. Longitudinal studies of VCFS children are currently under way to identify precursor symptoms and areas of dysfunction which precede the later development of major psychiatric disorder. Identification of such prodromal features in VCFS may have enormous implications for the clinical management of major psychiatric disorder in VCFS and in the wider population.

Abnormalities, Multiple↗
PubMed1990

Old syndromes and new cytogenetics.

This annotation has been confined to well-established clinical syndromes with recently discovered chromosomal etiologies. It deliberately omits retinoblastoma, the oft-cited paradigm of a contiguous gene syndrome, since it is usually inherited as a Mendelian single gene disorder. However, it was recognition of both the deletion of band q14 of chromosome 13 in mentally retarded children with retinoblastoma, and the linkage of retinoblastoma with the genetic marker esterase D, which resulted in the eventual cloning of the gene. Also omitted are microdeletions of the X chromosome. These disorders are seen primarily in males, who manifest the phenotypic effects of the deletion of the loci of various combinations of adjacent genes: Duchenne muscular dystrophy, glycerol kinase deficiency, adrenal hypoplasia, optic albinism, hypogonadotropic hypogonadism and anosmia (Kallman syndrome), chondrodysplasia punctata and ichthyosis. Many are also mentally retarded. The third group omitted are Mendelian disorders occurring with atypical mental retardation (not usually part of the disorder), the presumption being that they include small deletions. It is expected that other contiguous gene syndromes will be recognized eventually; Rubinstein-Taybi and Cornelia de Lange syndromes are prime candidates. Why do deletions have such dramatic consequences when a normal homologue of the region is present? If their effects were due to the uncovering of recessive genes, we would expect to see greater variations in phenotype among carriers, including normal individuals whose deletions were masked by the protective effects of dominant alleles in the homologous regions. Imprinting--the 'stamping' of a gene as it passes through the germ line--provides a more satisfactory explanation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Multiple↗
PubMed1996

p16INK4/p15INK4B gene inactivation is a frequent event in malignant T-cell lines.

The cell cycle regulators p16INK4 and p15INK4B have been mapped to the minimal region of overlap for chromosome 9p21 deletions, observed in a number of malignancies, suggesting that they could be tumor suppressor genes (TSGs). In the case of p16INK4 this has been further substantiated by the finding of small intragenic mutations. In this study we have investigated the p16INK4 and p15INK4B genes in 16 malignant T-cell lines by means of Southern blot, PCR and sequence analysis. p16INK4 allelic deletions occurred in 15 of 16 cell lines; 12 of which were homozygous and 3 hemizygous. In 1 cell line (DND 41) the remaining p16INK4 allele carried a microdeletion of 29 bp of exon 2, supporting the concept that p16INK4 is a target TSG for deletions on 9p21. Most p16INK4 deletions also included the p15INK4B gene. However, 4 of the cell lines deleted for p16INK4 showed no evidence of p15INK4B loss, indicating that p15INK4B is not the target in these cell lines.

Base Sequence↗
PubMed1994

Mutations in the phenylalanine hydroxylase gene: methods for their characterization.

Mutations in the phenylalanine hydroxylase (PAH) gene represent the root cause of PAH-deficient hyperphenylalaninemia. To date, more than 160 different mutations have been reported. Single-base substitutions and microdeletions account for the majority of molecular defects. This review provides a brief general introduction to various strategies for detection of PAH mutations, and summarizes our own methodological developments. We have established a method based on PCR in combination with denaturing gradient gel electrophoresis (DGGE) for mutation scanning of the entire coding sequence and all exon/intron boundaries of the PAH. Systematic application of this method to the study of a large number of mutant chromosomes from hyperphenylalaninemic patients demonstrated a 98% diagnostic efficiency and a 100% mutation detection efficiency. We have created compromised PCR and DGGE conditions for simultaneous amplification and simultaneous mutation scanning of all PAH-coding fragments. This technique is convenient in a diagnostic setting and allows "same-day" DNA-based diagnosis of newborns with hyperphenylalaninemia. A further modification of the method allows unambiguous identification of known mutations, circumventing the cumbersome step of nucleotide sequencing.

DNA Mutational Analysis↗
PubMed1997

The genetic basis for Prader-Willi syndrome: the importance of imprinted genes.

The genetic basis of Prader-Willi syndrome involves imprinted genes on the proximal long arm of chromosome 15. The basic defect appears to be the absence of function of genes that are normally expressed in a monoallelic fashion only from the paternal chromosome. In 60-70% of patients with Prader-Willi syndrome, the genetic defect is a deletion in the area of 15q11-13 on the paternal chromosome. A further 25-30% of patients with Prader-Willi syndrome do not have paternal deletions, the defect being due to uniparental disomy (UPD) for maternal chromosome 15. Paternal deletions and maternal UPD are functionally equivalent, as they both result in the absence of a paternal contribution to the genome in the 15q11-13 region. The SNRPN (small nuclear ribonucleoprotein-associated polypeptide N) gene has a critical role in the 15q11-13 region, as it is probably part of the putative imprinting centre that regulates the expression of several genes in the Prader-Willi syndrome transcriptional domain. Two further rare causes of Prader-Willi syndrome are imprinting mutations, which are microdeletions or point mutations in the putative imprinting control region, and translocations with their breakpoints in the Prader-Willi syndrome region.

Chromosome Aberrations↗
PubMed1993

Growth suppression of normal mammary epithelial cells by wild-type p53.

We examined the status of the p53 gene in the HC11 normal mammary epithelial cells. Two mutations were identified: a Cys to Trp change at codon 138 and a microdeletion of codon 123 to 130 resulting from mutation of the splice acceptor site. These two mutations were independent, and no wild-type p53 allele was found. Introduction of wt-p53 strongly inhibited growth in monolayer. Thus, the absence of wt-p53 can be sufficient for the immortalization of mammary cells.

Amino Acid Sequence↗
PubMed1994

Glucocorticosteroid resistance in humans. Elucidation of the molecular mechanisms and implications for pathophysiology.

Familial glucocorticoid resistance (FGR) is a rare hereditary disorder characterized by hypercortisolism and the absence of stigmata of Cushing's syndrome. The inability of glucocorticoids to exert their effects on target tissues is compensated for by increases in circulating corticotropin (ACTH) and cortisol, the former causing excess secretion of both adrenal androgens and adrenal steroid-biosynthesis intermediates with salt-retaining activity. There is considerable variability in the clinical presentations of FGR ranging from asymptomatic, to isolated chronic fatigue and to hypertension with or without hypokalemic alkalosis or to hyperandrogenism, or both. In women, hyperandrogenism can result in acne, hirsutism, menstrual irregularities, oligoanovulation, and infertility; in men it may lead to infertility and in children to precocious puberty. The reported molecular defects in FGR, such as point mutations and a microdeletion of the glucocorticoid receptor (GR) gene, cause partial resistance by, respectively, compromising the function of the GR or decreasing its intracellular concentration in glucocorticoid target tissues. Complete glucocorticoid resistance is believed to be incompatible with life in humans. Hence, the glucocorticoid resistance cases reported have been partial and of variable degree. The extreme variability in the clinical manifestations of the disorder can, additionally, be explained by differing sensitivity of target tissues to mineralocorticoids or androgens or both, and perhaps by different biochemical defects of the glucocorticoid receptor, causing selective resistance of certain glucocorticoid responses in specific tissues. Isolated tissue-resistance from a somatic mutation of the GR in a corticotropinoma from a patient with Nelson's syndrome was also found, suggesting that this may be a mechanism of tumorigenesis. There is additional evidence that defects of GR function can appear surreptitiously in a variety of clinical conditions, suggesting that glucocorticoid resistance in humans may be involved in the pathogenesis and/or clinical picture of a plethora of disease states, of which FGR is the archetype.

Adrenocorticotropic Hormone↗
PubMed2005

GTF2IRD1 in craniofacial development of humans and mice.

Craniofacial abnormalities account for about one-third of all human congenital defects, but our understanding of the genetic mechanisms governing craniofacial development is incomplete. We show that GTF2IRD1 is a genetic determinant of mammalian craniofacial and cognitive development, and we implicate another member of the TFII-I transcription factor family, GTF2I, in both aspects. Gtf2ird1-null mice exhibit phenotypic abnormalities reminiscent of the human microdeletion disorder Williams-Beuren syndrome (WBS); craniofacial imaging reveals abnormalities in both skull and jaws that may arise through misregulation of goosecoid, a downstream target of Gtf2ird1. In humans, a rare WBS individual with an atypical deletion, including GTF2IRD1, shows facial dysmorphism and cognitive deficits that differ from those of classic WBS cases. We propose a mechanism of cumulative dosage effects of duplicated and diverged genes applicable to other human chromosomal disorders.

Adolescent↗
PubMed1997

Dynamic molecular combing: stretching the whole human genome for high-resolution studies.

DNA in amounts representative of hundreds of eukaryotic genomes was extended on silanized surfaces by dynamic molecular combing. The precise measurement of hybridized DNA probes was achieved directly without requiring normalization. This approach was validated with the high-resolution mapping of cosmid contigs on a yeast artificial chromosome (YAC) within yeast genomic DNA. It was extended to human genomic DNA for precise measurements ranging from 7 to 150 kilobases, of gaps within a contig, and of microdeletions in the tuberous sclerosis 2 gene on patients' DNA. The simplicity, reproducibility, and precision of this approach makes it a powerful tool for a variety of genomic studies.

Calpain↗
PubMed1999

A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects.

Microdeletions of chromosome 22q11 are the most common genetic defects associated with cardiac and craniofacial anomalies in humans. A screen for mouse genes dependent on dHAND, a transcription factor implicated in neural crest development, identified Ufd1, which maps to human 22q11 and encodes a protein involved in degradation of ubiquitinated proteins. Mouse Ufd1 was specifically expressed in most tissues affected in patients with 22q11 deletion syndrome. The human UFD1L gene was deleted in all 182 patients studied with 22q11 deletion, and a smaller deletion of approximately 20 kilobases that removed exons 1 to 3 of UFD1L was found in one individual with features typical of 22q11 deletion syndrome. These data suggest that UFD1L haploinsufficiency contributes to the congenital heart and craniofacial defects seen in 22q11 deletion.

Adaptor Proteins, Vesicular Transport↗
PubMed2003

Hypoparathyroidism and 22q11 deletion syndrome.

AIMS: To investigate a population of individuals with 22q11 deletion syndrome for hypocalcaemia. METHODS: A detailed clinical history enquiring into symptoms of hypocalcaemia and blood sampling to assess for hypocalcaemia and hypoparathyroidism, of patients outside the neonatal period known to have the 22q11 microdeletion from fluorescent in situ hybridisation studies was taken. RESULTS: Sixty one individuals were identified, of whom 23 were untraceable and one was unable to give informed consent. Biochemical investigations were performed on 27 subjects. Ten subjects had review of notes only. Four subjects had previously identified hypoparathyroidism. A new case of hypoparathyroidism was identified. Three subjects had borderline hypocalcaemia. DISCUSSION: In this population of patients with 22q11 deletion syndrome, 13% of the total or 30% of those biochemically assessed had evidence of reduced serum calcium concentrations. It is likely that 13-30% of patients with 22q11 deletion syndrome have possible hypoparathyroidism outside the neonatal period. Reported symptoms of hypocalcaemia did not correlate with biochemical evidence of persisting hypocalcaemia. We have shown that previously undiagnosed asymptomatic hypoparathyroidism occurs in patients with 22q11 deletion syndrome and conclude that screening of this population should be considered.

Adolescent↗
PubMed2004

An atypical phenotype of macular and peripapillary retinal atrophy caused by a mutation in the RP2 gene.

AIMS: To determine the molecular basis and describe the phenotype of an atypical retinal dystrophy in a family presenting with bilateral, progressive central visual loss. METHODS: Family members were examined. Investigations included Goldman perimetry, electrophysiology, and autofluorescence imaging. Candidate gene screening was performed using SSCP and sequence analysis. The proband's lymphoblastoid cells were examined for protein expression. RESULTS: Fundal examination of the proband, his mother, and brother revealed peripapillary and macular atrophy. Autosomal dominant retinal dystrophy was suspected, but less severe disease in the mother led to screening for mutations in X linked genes. A 4 bp microdeletion in exon 3 of the RP2 gene, segregating with disease, was identified. No RP2 protein expression was detected. CONCLUSION: The distinct phenotype in this family, caused by this frameshifting mutation in RP2, broadens the phenotypic spectrum of X linked retinitis pigmentosa. The absence of RP2 protein suggests that loss of protein function and not novel gain of function could account for the atypical phenotype. A definitive diagnosis of X linked retinitis pigmentosa permits appropriate genetic counselling with important implications for other family members. Clinicians should have a low threshold for screening RP2 in families with retinal dystrophy, including posterior retinal disease, not immediately suggestive of X linked inheritance.

Adult↗
PubMed1996

Isomerism of the atrial appendages associated with 22q11 deletion in a fetus.

There is a strong association between prenatally diagnosed structural heart disease and fetal chromosomal abnormalities. Isomerism of the atrial appendages is an exception to this because the fetal karyotype is usually normal in this condition. A case of atrial isomerism diagnosed antenatally with a normal female karyotype but with a microdeletion of chromosome 22q11 is reported.

Adult↗
PubMed1998

Monosomy 22q11 in patients with pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries.

OBJECTIVE: To describe the morphology of the pulmonary arteries in patients with pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries with and without monosomy 22q11. DESIGN: A retrospective analysis of all patients with this congenital heart defect who are being followed at the University Children's Hospital Erlangen. SETTING: A tertiary referral centre for paediatric cardiology and paediatric cardiac surgery. PATIENTS: 21 patients with pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries. Monosomy 22q11 was diagnosed by fluorescent in situ hybridisation using the D22S75 probe (Oncor). The morphology of the pulmonary arteries was assessed on the basis of selective angiograms. RESULTS: 10 patients (48%) were shown to have a microdeletion in 22q11 (group I). There was no difference with respect to the presence of confluent central pulmonary arteries between these patients (80%) and the remaining 11 patients (group II) without monosomy 22q11 (91%). Patients of group I, however, more often had arborisation anomalies of the pulmonary vascular bed (90% in group I v 27% in group II). Because of the more severe abnormalities of the pulmonary arteries, a biventricular repair had not been possible in any of the children with monosomy 22q11, though repair had been carried out in 64% of the children in group II. CONCLUSION: The developmental disturbance caused by the monosomy 22q11 seems to impair the connection of the peripheral pulmonary artery segments to the central pulmonary arteries in patients with pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries, resulting in a lower probability of biventricular repair.

Adolescent↗