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PubMed1996

Factor XIII(A) subunit deficiency due to a homozygous 13-base pair deletion in exon 3 of the A subunit gene.

We investigated the molecular basis of factor XIII(A) subunit deficiency in a Greek family. Each of the 15 exons of the A subunit gene were individually amplified by polymerase chain reaction, using previously reported oligoprimers. The proband with severe deficiency was found to have a homozygous 13-base pair deletion in the 3' half of exon 3. The deleted sequence, extending from codons 82-86, results in a frameshift and generates a downstream termination codon in exon 4. Single strand conformation polymorphism (SSCP) analysis detected no additional mutations in the coding or consensus splice sequences of the A subunit gene. Both parents of the proband were heterozygous for the defect. Only one previous microdeletion (AG dinucleotide) has been reported in the A subunit gene, and was located at the intron B-exon 3 boundary. Further studies are necessary to determine whether this region of the gene is a "hot spot" for microdeletion mutations.

Amino Acid Sequence↗
PubMed1999

Molecular studies in 20 submicroscopic neurofibromatosis type 1 gene deletions.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized by a marked variability in expression. A more severe phenotype is frequently observed in the group of patients carrying a large NF1 deletion. To study the extent of the microdeletion in these NF1 patients, we generated a partial physical map of the NF1 flanking region. We describe seven PACs and three new polymorphic dinucleotide repeats located outside the NF1 gene and analyzed 20 unrelated individuals with an NF1 microdeletion in a collaborative study. We detected one individual with a substantially smaller deletion including only the NF1 gene and its three embedded genes. In the other 19 patients, the deletion extended at least 1 Mb. The parental origin of the deletion was determined in 15 individuals and was maternal in 13 and paternal in two cases. The new molecular tools described here can be used to unequivocally diagnose a possible extragenic extension of an NF1 deletion.

Base Sequence↗
PubMed2002

Prader Willi/Angelman and DiGeorge/velocardiofacial syndrome deletions: diagnosis by primed in situ labeling (PRINS).

A recently developed methodology-primed in situ labeling (PRINS)-can be used in place of fluorescence in situ hybridization (FISH) to diagnose microdeletions. To demonstrate the efficiency, sensitivity, and specificity of PRINS in the diagnosis of microdeletions, we studied groups of patients with Prader Willi/Angelman (PWS/AS) syndrome and DiGeorge/velocardiofacial syndrome (DGS/VCFS). Results obtained by PRINS were then confirmed with the results obtained with FISH. Oligonucleotide primers specific for SNRPN and GABRB3 were used for PWS/AS syndromes. For DGS/VCFS, the primers used were DGCR2/TUPLE1 loci. Labeling patterns obtained by PRINS and FISH were analyzed and scored under a fluorescence microscope. Five normal subjects served as controls and were used for standardization of the PRINS protocol. In all, 20 study patients were involved: 10 PWS/AS and 10 DGS/VCFS. Five of the 10 patients referred with the clinical diagnosis of PWS/AS showed absence of labeling for SNRPN and GABRB3 on one chromosome 15, confirming deletion of the two loci. Similarly, 6 of the 10 patients referred for DGS/VCFS showed deletion for the DGCR2/TUPLE1 loci on one chromosome 22. The remaining patients and controls had normal patterns for all the loci as indicated by FISH and PRINS. Concordant FISH and PRINS results were obtained in all patients and controls studied.

Angelman Syndrome↗
PubMed2001

Deletions at chromosome regions 7q11.23 and 7q36 in a patient with Williams syndrome.

We report on a patient with Williams syndrome and a complex de novo chromosome rearrangement, including microdeletions at 7q11.23 and 7q36 and additional chromosomal material at 7q36. The nature of this additional material was elucidated by spectral karyotyping and first assigned to chromosome 22. Subsequent fluorescence in situ hybridization (FISH) experiments showed that it consisted of satellite material only. Refinement of the 7q36 breakpoint was performed with several FISH probes, showing a deletion distal to the triphalangeal thumb (TPT) region. The phenotype of the patient principally results from the microdeletion of the 7q11.23; the small deletion at 7qter and the extra satellite material may not be of clinical significance.

Adult↗
PubMed2003

DiGeorge/velocardiofacial syndrome: FISH studies of chromosomes 22q11 and 10p14, and clinical reports on the proximal 22q11 deletion.

DiGeorge anomaly/velocardiofacial syndrome (DG/VCFS) occurs with different deletion intervals on chromosomes 22q11, while the DiGeorge anomaly (with other findings) is seen in patients with deletions of 10p14. The clinical outcome with the common 22q11 deletion (90% of cases) is well known, but the outcome with the less frequent deletion types has not been well documented. Using cytogenetic and fluorescence in situ hybridization (FISH) analysis we studied a series of 295 patients with suspected DG/VCFS. We identified 58 subjects with a 22q11 deletion, and none with a 10p deletion. Fifty-two subjects had the common deletion, five had the proximal deletion, and one had an atypical proximal deletion due to a 1;22 translocation. We report clinical data of four subjects with the proximal 22q11 microdeletion, and of one patient with the atypical proximal deletion. The anomalies observed with the proximal 22q11 microdeletion fell within the DG/VCFS spectrum. Two females, 6 and 25 years old, had normal mental development. Normal development has been reported with the common 22q11 deletion, but only in a minority of cases. This study may indicate a better intellectual and/or behavioral outcome with the proximal vs. the common 22q11 deletion, rather than a chance finding.

Abnormalities, Multiple↗
PubMed2003

Toward a genetic etiology of CHARGE syndrome: I. A systematic scan for submicroscopic deletions.

CHARGE syndrome is a distinctive subgroup within the more heterogeneous group of patients with CHARGE association. While significant progress has been made in the clinical delineation of this syndrome, the molecular basis of the disorder remains unknown. Based on the complex phenotype, some overlap with DiGeorge/velocardiofacial syndrome (DGS/VCFS), and its estimated population incidence, we hypothesized that CHARGE syndrome could be caused by an unidentified genomic microdeletion. In order to address this hypothesis, we carried out a genome-wide screen for loss of expected heterozygosity using 811 microsatellite markers in ten CHARGE syndrome subjects and their unaffected parents. Eight markers gave results suggestive of failure to inherit one parental allele. These loci were tested with fluorescence in situ hybridization (FISH), but none showed evidence of deletion. This screen sets upper limits on the length of a CHARGE-related microdeletion, should that be the genetic mechanism underlying the phenotype.

Alleles↗
PubMed2005

Higher frequency of uncommon 1.5-2 Mb deletions found in familial cases of 22q11.2 deletion syndrome.

Familial 22q11.2 deletions have been reported as a 6%-28% of the total affected cases of 22q11.2 microdeletion syndrome (del22q11.2). Different deletion genotypes have been described for this disorder, with a predominant 3 Mb deletion present in 90% of the cases, a less common 1.5-2 Mb deletion in 8%, and atypical smaller deletions in 2%. We have studied 15 cases of del22q11.2 from 6 families (two of them three-generation families) that were previously diagnosed through FISH. We have sized the deleted region by allele genotyping of 12-16 polymorphic markers in all cases, and we have found three families affected with the 1.5-2 Mb deletion, two affected with the 3 Mb deletion, and one in which the deletion size could not be determined. This predominance of the smaller 1.5-2 Mb deletions in our familial cases differs from the minor frequency observed in sporadic cases of del22q11.2. This finding suggests that small deletions are more linked to familial inheritance than large ones, possibly due to psychosocial or biological factors associated with differences in the phenotype. Deletion sizing on routine diagnosis may help characterizing the inheritability of 22q11.2 microdeletion syndrome.

Abnormalities, Multiple↗
PubMed2006

Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation.

The underlying cause of mental retardation remains unknown in up to 80% of patients. As chromosomal aberrations are the most common known cause of mental retardation, several new methods based on FISH, PCR, and array techniques have been developed over recent years to increase detection rate of subtle aneusomies initially of the gene rich subtelomeric regions, but nowadays also genome wide. As the reported detection rates vary widely between different reports and in order to compare the diagnostic yield of various investigations, we analyzed the diagnostic yield of conventional karyotyping, subtelomeric screening, molecular karyotyping, X-inactivation studies, and dysmorphological evaluation with targeted laboratory testing in unselected patients referred for developmental delay or mental retardation to our cytogenetic laboratory (n = 600) and to our genetic clinic (n = 570). In the cytogenetic group, 15% of patients showed a disease-related aberration, while various targeted analyses after dysmorphological investigation led to a diagnosis in about 20% in the genetic clinic group. When adding the patients with a cytogenetic aberration to the patient group seen in genetic clinic, an etiological diagnosis was established in about 40% of the combined study group. A conventional cytogenetic diagnosis was present in 16% of combined patients and a microdeletion syndrome was diagnosed in 5.3%, while subtelomeric screening revealed only 1.3% of causes. Molecular karyotyping with a 10 K SNP array in addition revealed 5% of underlying causes, but 29% of all diagnoses would have been detectable by molecular karyotyping. In those patients without a clear diagnosis, 5.6% of mothers of affected boys showed significant (>95%) skewing of X-inactivation suggesting X-linked mental retardation. The most common diagnoses with a frequency of more than 0.5% were Down syndrome (9.2%), common microdeletion 22q11.2 (2.4%), Williams-Beuren syndrome (1.3%), Fragile-X syndrome (1.2%), Cohen syndrome (0.7%), and monosomy 1p36.3 (0.6%). From our data, we suggest the following diagnostic procedure in patients with unexplained developmental delay or mental retardation: (1) Clinical/dysmorphological investigation with respective targeted analyses; (2) In the remaining patients without an etiological diagnosis, we suggest conventional karyotyping, X-inactivation screening in mothers of boys, and molecular karyotyping, if available. If molecular karyotyping is not available, subtelomeric screening should be performed.

Child, Preschool↗
PubMed2004

An investigation into sub-telomeric deletions of chromosome 22 and pervasive developmental disorders.

Deletions of the sub-telomeric region of chromosome 22 have been associated with mental retardation, developmental delay, and autistic behaviors. This study investigated sub-telomeric anomalies of chromosome 22 using fluorescent in situ hybridization (FISH) probes in 82 subjects diagnosed with autism and atypical autism. No microdeletions were detected in this group. Similar FISH analyses were undertaken on two children with developmental delay, who were ascertained to be ring 22 during routine cytogenetic investigations. One subject was shown to have a microdeletion in the sub-telomeric region tested. Both children met the social and communication cut off for autism on the ADI and but did not meet the cut off for restrictive and repetitive behaviors. Only one of the two children met the criteria for PDD on the ADOS.

Child↗
PubMed2004

Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome.

The study of neurogenetic microdeletion syndromes provides an insight into the developmental psychopathology of psychiatric disorders. The aim of the study was to evaluate the prevalence of psychiatric disorders, especially obsessive-compulsive disorder (OCD), in patients with velocardiofacial syndrome (VCFS), a 22q11 microdeletion syndrome. Forty-three subjects with VCFS of mean age 18.3 +/- 10.6 years were comprehensively assessed using semi-structured psychiatric interview and the Yale-Brown obsessive compulsive scale (Y-BOCS). Best estimate diagnoses were made on the basis of information gathered from subjects, parents, teachers, and social workers. Fourteen VCFS subjects (32.6%) met the DSM-IV criteria for OCD. OCD had an early age of onset and generally responded to fluoxetine treatment. It was not related to mental retardation. The most common obsessive-compulsive symptoms were contamination, aggression, somatic worries, hoarding, repetitive questions, and cleaning. Sixteen of the 43 patients (37.2%) had attention-deficit/hyperactivity disorder (ADHD), and 7 (16.2%) had psychotic disorder. The results of our study suggest that there is a strong association between VCFS and early-onset OCD. This finding may be significant in the understanding of the underlying genetic basis of OCD.

Adolescent↗
PubMed2004

COMT: a common susceptibility gene in bipolar disorder and schizophrenia.

A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11-a region which includes the catechol-O-methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases--and probably also a wider range of behavioral traits.

Bipolar Disorder↗
PubMed2003

Complete physical map and gene content of the human NF1 tumor suppressor region in human and mouse.

Duplicon-mediated microdeletions around the NF1 gene are frequently associated with a severe form of neurofibromatosis type I in a subgroup of patients who show an earlier onset of cutaneous neurofibromas, dysmorphic facial features, and lower IQ values. To clarify the discrepancies between published maps of the NF1 tumor-suppressor gene region as well as the length of gaps in these assemblies and to validate the recently described tandem duplication of the human NF1 locus, we assembled a contiguous high-density map of BAC and PAC clones from different genomic libraries. Although two WI-12393-derived low-copy fragments are known to occur at the proximal and distal boundaries of the 1.5-Mb segment that is usually deleted in NF1 microdeletion patients, we identified an additional WI-12393-related segment between the MGC13061 and the NF1 gene, which appears to trigger interstitial deletions of smaller size as observed in two patients. Moreover, we completed the genomic organization and cDNA structure of all functional genes, CYTOR4, FLJ12735, FLJ22729, CENTA2, MGC13061, NF1, OMG, EVI2B, EVI2A, KIAA1821, MGC11316, HCA66, KIAA0160, and WI-12393, from this region. A comparison of the human map to the orthologous region on mouse chromosome 11 revealed significant differences in the number and arrangement of genes, indicating that many chromosomal breaks with partial duplications, inversions, and deletions occurred predominantly in the primate lineage.

Adult↗
PubMed2001

Identification of four novel polymorphisms in the calcitonin/alpha-CGRP (CALCA) gene and an investigation of their possible associations with Parkinson disease, schizophrenia, and manic depression.

We identified novel polymorphisms in the calcitonin/CGRPalpha (CALCA) gene by direct sequencing of genomic DNA and subsequent genotyping by RFLP (restriction fragment length polymorphism) detection and investigated association with neurological or psychiatric disease. Four novel polymorphic alleles were found: two (g.979G>A and g.4218T>C) represented single nucleotide polymorphisms (SNPs), one consisted of two coupled SNPs in close vicinity to each other (g.1210T>C and g.1214C>G), and one was an intronic 16-bp microdeletion (2919-2934del16). One of the SNPs (g.4218T>C) causes a non-synonymous amino acid change (Leu66Pro) in the third exon, an exon common to both procalcitonin and pro-alpha-CGRP. In a subsequent association study, frequencies of the identified polymorphisms in Parkinson and schizophrenia patients were compared with frequencies in the normal population. No statistically significant association was found in our material. The 16-bp microdeletion polymorphism was present in a family with multiple cases of unipolar or bipolar depressive disorder. Using this polymorphism as marker, cosegregation with the phenotype was observed in the majority of individuals.

Amino Acid Sequence↗
PubMed2006

Preferential occurrence of 1-2 microindels.

Microindels are unique, infrequent mutations that result in inserted and deleted sequences of different sizes (between one and 50 nucleotides) at the same nucleotide position. Little is known about the mutational mechanisms that are responsible for these mutations. From our database of 6,016 independent somatic mutational events in the lacI gene in Big Blue mice, we assembled the 30 microindels (0.5%) for analysis. Microindels with one nucleotide inserted and two nucleotides deleted (1-2 microindels) accounted for seven (23%) of the microindels observed, with the remaining microindels distributed among 21 other combinations of insertion and deletion sizes. A preferential occurrence of 1-2 microindels (20%) was also observed in human germline transmitted mutations in the Human Gene Mutation Database (HGMD). An examination of the sequence flanking the mouse 1-2 microindels did not reveal obvious site specificity or associated secondary structure. A detailed examination of 1-2 microindels did not reveal the features typical of pure microinsertion and microdeletion events, but rather suggested a unique mutational mechanism. The 1 bp insertion in 1-2 microinsertions, and pure 1 bp insertions show distinct features. The mechanism for 1-2 microindels is not obviously a simple combination of pure microinsertion and microdeletion events. The dramatic enhancement of 1-2 microindels requires explanation. We speculate that certain error-prone polymerases may be responsible for the preferential occurrence of 1-2 microindels in both somatic tissues and germ cells. It is estimated that a human adult carries roughly 400 billion somatic 1-2 microindels with the potential to predispose to cancer.

Animals↗
PubMed2003

Complete loss of HLA class I antigen expression on melanoma cells: a result of successive mutational events.

Alterations in the surface expression of HLA class I molecules have been described as a strategy of tumors to evade recognition by cytotoxic T cells. We detected complete loss of HLA class I antigen presentation for 2 tumor cell lines from 1 melanoma patient, the first originated from a regional lymph node lesion diagnosed simultaneously with the primary tumor and the second established 8 months later from a metastatic pleural effusion sample. Antigen presentation was not inducible with IFN-gamma but could be restored after transfection of tumor cells with b2m cDNA, indicating a defect in b2m expression. Analysis of the nature of this defect revealed that it originated from at least 2 mutational events affecting both copies of the b2m gene: a microdeletion of 498 bp in one b2m gene, including its entire exon 1, and a macrodeletion involving the entire copy of the second b2m gene. Microsatellite analysis pointed to the macrodeletion by demonstrating LOH for several specific markers on the long arm (q) of chromosome 15. Structural imbalance of 15q was verified by FISH. FISH studies also indicated the coexistence of a structurally abnormal variant of chromosome 15q with 2 apparently entire chromosomes 15q harboring the homozygous b2m microdeletion. Block of b2m expression in tumor cells builds a barrier to immunotherapy of cancer patients, and its early incidence should be of major consideration in the development and design of immunotherapeutic strategies.

Adult↗
PubMed2002

Alterations of the INK4a-ARF gene locus in pleomorphic adenoma of the parotid gland.

Pleomorphic adenomas of the parotid gland are benign tumours composed of epithelial and mesenchymal cells. The INK4a-ARF (CDKN2A) locus on chromosome 9p21 encodes two tumour suppressor proteins, p16(INK4a) and p14(ARF), which act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway in pleomorphic adenomas, this study analysed alterations of p14(ARF), p16(INK4a), p53, and pRb in these tumours. After microdissecting the different histological components, 42 pleomorphic adenomas of the parotid gland were analysed for INK4a-ARF inactivation by DNA sequence analysis, methylation-specific PCR (MSP), restriction enzyme-related polymerase chain reaction (RE-PCR), mRNA expression, microsatellite analysis, and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INK4a) were assessed by differential PCR. The status of p53 and Rb was examined by direct sequencing and immunohistochemistry. Using microdissection, it was possible to examine the tumour components, i.e. epithelial, mesenchymal, and transitional, separately after immunohistochemical identification. Methylation of p14(ARF) was found in 1/42 cases and alterations of p16(INK4a) occurred in 12/42 of pleomorphic adenomas, which correlated with loss of mRNA transcription. Microdeletions or specific mutations of either exon were not detected. Methylation was detected exclusively in the epithelial and transitional components and not within the mesenchymal part of the tumour. p53 mutations were detected in 4/42 adenomas, also occurring solely in the epithelial components of the tumours. pRb was detected immunohistochemically in 40/42 adenomas. In normal, corresponding parotid tissue, p14(ARF), p16(INK4a), p53, and pRb alterations were not observed. The observation that alterations of p14(ARF) and p16(INK4a), and also p53 mutations, occurred exclusively in the epithelial and transitional components of pleomorphic adenoma supports the theory that these areas are prone to malignant transformation to carcinoma in adenoma.

Adenoma, Pleomorphic↗
PubMed2006

Prenatal diagnosis and outcome for fetuses with congenital absence of the pulmonary valve.

OBJECTIVES: To analyze fetal echocardiographic findings of absent pulmonary valve syndrome (APVS), its association with chromosomal and extracardiac anomalies including nuchal translucency (NT) and the outcome after diagnosis. METHODS: Data of 14 fetuses with confirmed APVS retrospectively collected in two tertiary referral centers between 1998 and 2004 were analyzed. The variables examined were: reason for referral, gestational age at diagnosis and associated abnormalities, including first trimester NT thickness. Cardiac evaluation included measurement of cardiothoracic ratio, diameter of pulmonary arteries and Doppler flow in the pulmonary trunk. Information was retrieved from clinical files, recorded videotapes and stored images. Karyotyping including examination for the 22q11 deletion was performed in all cases. RESULTS: Mean gestational age at diagnosis was 28 weeks, with 5/14 (36%) diagnosed before 22 weeks. In 13/14 (93%) there was an associated ventricular septal defect (subaortic in 12 fetuses and inlet-type in one) and all 13 had tetralogy of Fallot. Enlargement of the central pulmonary arteries and cardiomegaly were present in all cases diagnosed after 22 weeks. Of the five fetuses in which APVS was detected before 22 weeks, four (80%) had a normal pulmonary trunk diameter, two (40%) had normal pulmonary branches and three (60%) had normal cardiac size. The arterial duct was absent in 11/14 (79%). A correlation between presence of the arterial duct and the size of the central pulmonary arteries or cardiomegaly could not be established. Increased NT was observed in 4/10 cases (40%) for which this information was available. 22q11 microdeletion was diagnosed in three fetuses (21%). There were five terminations of pregnancy, one intrauterine death, five neonatal deaths and one infant death. Of the six neonates with respiratory distress, only one (17%) survived and of the eight babies in whom there was an intention to treat, two survived (25%). CONCLUSIONS: APVS can be accurately diagnosed by fetal echocardiography but screening ultrasound in the mid-second trimester is likely to have a low detection rate, probably due to the incomplete expression of the disease at this point. Many fetuses with APVS have an increased NT in the first trimester and this may help an earlier recognition of the defect. The most common associated karyotype anomaly is 22q11 microdeletion. Enlargement of the central pulmonary arteries is mainly related to the gestational age at diagnosis. Our results confirm that the outlook for these patients is extremely poor.

Adult↗