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PubMed2006

Right aortic arch in the fetus.

OBJECTIVE: To examine our experience of the detection of a right aortic arch in the fetus over an 8-year period. METHODS: Between February 1998 and December 2005, all patients prospectively diagnosed with a right aortic arch at our center were identified from our database and the videotape reviewed. In addition, the videotapes of 300 normal and 110 abnormal arbitrarily selected fetal echocardiograms, as well as 123 cases of tetralogy of Fallot and nine of a common arterial trunk were reviewed. Data including indication for fetal echocardiography, gestational age at diagnosis, karyotype, nuchal translucency measurement and outcome were collected. RESULTS: A right aortic arch was diagnosed prospectively in 55 fetuses and in a further 20 on retrospective videotape review. There were 21 examples of isolated aortic arch and four thought to have a double arch. A right arch was found in association with additional intracardiac malformations in 50 cases. The detection rate of a right aortic arch increased over the study period. The majority of patients were referred for a suspicion of congenital heart disease on obstetric scanning. Mean gestational age at diagnosis was 21 weeks. The karyotype including 22q11 status was known in 45/75 cases. There were 23 confirmed karyotypic anomalies, 12 of which were 22q11 deletions, occurring in 2/25 of the isolated group and 10/48 of the complex group, with a further two complex cases that were likely to have had 22q11 microdeletions. There were 29 pregnancy interruptions, four intrauterine deaths, 31 live births, four neonatal deaths and three patients lost to follow-up. The remaining four pregnancies are continuing. Of the four with suspected double arch, three were confirmed postnatally. CONCLUSION: The diagnosis of a right-sided aortic arch can be made by fetal echocardiography, either as an isolated lesion or in association with other cardiac malformations, from as early as 12 weeks' gestation. It can be difficult to distinguish from a double arch. Its increasing incidence over time in our series probably indicates that the diagnosis was previously overlooked. Karyotyping in the absence of other abnormal findings may be unnecessary in every case, but establishment of 22q11 microdeletion status in those cases with other anomalies is important.

Aorta, Thoracic↗

PubMed2006

Right aortic arch detected in fetal life.

OBJECTIVE: To evaluate the prenatal distribution, associated conditions and outcome of the different types of right aortic arch (RAA) detected in fetal life. METHODS: This was a retrospective review of all cases of RAA detected prenatally between 1998 and 2005 in two tertiary referral centers. RESULTS: In the study period 71 cases of RAA were detected; 26 (37%) had RAA with aberrant left subclavian artery, 23 (32%) had RAA with mirror-image branching, 20 (28%) had RAA of unknown type and two (3%) had double aortic arch. While 20/26 cases with RAA and aberrant left subclavian artery were isolated findings, all 23 cases with RAA and mirror-image branching were associated with cardiac defects, namely tetralogy of Fallot (43%) or pulmonary atresia with ventricular septal defect (22%). Of the 20 cases with RAA, 19 of unknown type were associated with heterotaxy syndromes and had additional cardiac malformations and ambiguities of the situs. The two cases with DAA were isolated findings. Seven cases in our series (10%) had a microdeletion 22q11 and these were significantly associated with extracardiac malformations. The outcome in our series depended solely on the associated cardiac and extracardiac malformations, with the exception of one infant with isolated DAA, in whom a surgical correction was warranted. CONCLUSIONS: RAA detected in fetal life is associated frequently with other cardiac/non-cardiac malformations, heterotaxy syndromes and microdeletions 22q11. The associated conditions vary depending on the branching type of the brachiocephalic vessels and the presence of extracardiac malformations.

Adult↗

PubMed1997

Human Y chromosome deletions in Yq11 and male fertility.

An overview is given about the current knowledge and research activities on the molecular analysis of interstitial deletions in the euchromatic part of the long arm of the human Y chromosome (Yq11). These mutations are associated with the male specific phenotype of azoospermia and severe oligozoospermia. The fact is stressed that only "de novo" microdeletions in Yq11 are of any diagnostic value in the infertility clinic because numerous polymorphic deletion events in Yq11 have also been reported. Three different "de novo" Yq11 microdeletions associated with male infertility are now found repeatedly (31 cases) in more than 700 patients. They strongly support the presence of at least three spermatogenesis loci in Yq11. They have been designated as AZFa, AZFb, and AZFc. Each of them should contain at least one Y gene functional in spermatogenesis and, if mutated, it should induce the same sterile phenotype as the corresponding AZF locus. These genes have not yet been found. However, some candidate genes exist: RBM for AZFb. DAZ and SPGY for AZFc. It is remarkable that all three encode testis specific RNA binding proteins with a similar sequence structure. Their structure and potential relationship is disussed.

Base Sequence↗

PubMed1993

Routine diagnosis of DiGeorge syndrome by fluorescent in situ hybridization.

In a series of ten patients affected by DiGeorge syndrome, we screened, by high resolution banding and fluorescent in situ hybridization of a cosmid probe, for microdeletions associated with this syndrome. In the ten patients, a microdeletion was demonstrated by in situ hybridization, but suspected only in two patients by high resolution banding.

Adult↗

PubMed1989

Characterization of patients with glycerol kinase deficiency utilizing cDNA probes for the Duchenne muscular dystrophy locus.

Genomic DNA from five previously unreported patients with glycerol kinase deficiency (GKD), dystrophic myopathy, and adrenal insufficiency were studied with genomic probes and cDNA probes for the Duchenne muscular dystrophy (DMD) locus. These individuals, together with those reported by ourselves and others, show that patients with a contiguous gene syndrome involving the DMD, GK, and adrenal hypoplasia congenita (AHC) loci have a broader distribution of microdeletion breakpoints than those observed among patients with classical DMD. This study demonstrates the use of the DMD cDNA probes to delineate the centromeric deletion breakpoints for patients with Xp21 microdeletions extending beyond the DMD locus. It also shows the practical diagnostic application of the DMD cDNA probes when the diagnosis of GKD is entertained in a patient with known DMD and only DNA is available for study.

Adolescent↗

PubMed1994

Deleted chromosome 20 from a patient with Alagille syndrome isolated in a cell hybrid through leucine transport selection: study of three candidate genes.

Alagille syndrome (AGS) is a well-defined genetic entity assigned to the short arm of Chromosome (Chr) 20 by a series of observations of AGS patients associated with microdeletions in this region. By fusing lymphoblastoid cells of an AGS patient that exhibited a microdeletion in the short arm of Chr 20 encompassing bands p11.23 to p12.3 with rodent thermosensitive mutant cells (CHOtsH1-1) deficient in-leucyl-tRNA synthetase, we isolated a somatic cell hybrid segregating the deleted human Chr 20. This hybrid clone, designated NR2, was characterized by several methods, including PCR, with eight pairs of oligonucleotides mapped to Chr 20: D20S5, D20S41, D20S42, D20S56, D20S57, D20S58, adenosine deaminase (ADA), and Prion protein (PRIP); Restriction Fragment Length Polymorphism (RFLP) analyses with four genomic anonymous probes (D20S5, cD3H12, D20S17, D20S18); and fluorescent in situ hybridization (FISH) with total human DNA and D20Z1, a sequence specific to the human Chr 20 centromere, as probes. The NR2 hybrid allowed us to exclude three candidate genes for AGS: hepatic nuclear factor 3 beta (HNF3 beta), paired box 1 (PAX1), and cystatin C (CST3) as shown by their localization outside of the deletion. The NR2 hybrid is a powerful tool for the mapping of new probes of this region, as well as for obtaining new informative probes specific for the deletion by subtractive cloning of the region. Such markers will be useful for linkage analysis and screening of cDNA libraries.

Alagille Syndrome↗

PubMed1990

Different type of hepatitis B virus (HBV) DNA integrants that may reflect the integration process.

Through analyses of HBV DNA integratns in human cellular DNA, we identified three different integrant types, each of which may reflect the process of primary integrant formation by the viral DNA. The first type, which we call "simple type" consists of integrants found in some hepatocellular carcinomas (HCC's). The structure of the viral genome is simple, and part of it is deleted. The viral cohesive end sequence appears at one of the viral-cellular DNA junctions, and integration has elicited a microdeletion in the target cellular DNA sequence. This structure suggests viral DNA replication intermediates as substrates for integration. Judging from its frequency in HCC, this type may represent the most preferred one, if not all, among the primary integration products. The second type, which we call "complex type" is essentially the same as the first type, except tht the viral genome structure is complex. We considered the possibility that they may have been produced via the same process, using preformed complex viral genomes such as "novel form DNA's" (Rogler and Summers, 1982) as substrates. In cultured fetal hepatocytes, integration of HBV DNA can occur only a few days after infection. Among such integrants, we found a third type integrant, having a simple viral genome, but having a larger cellular DNA deletion. We propose that different forms of viral DNA may be used as substrates in the integration process, and the process is characterized by its eliciting of deletions of different size in the target cellular DNA. The most preferred substrate may be the one producing the simple type integrants, and the most frequently occurring deletion in the target DNA may be the microdeletion.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

PubMed2000

A case of Miller-Dieker syndrome in a family with neurofibromatosis type I.

The Miller-Dieker syndrome (type I lissencephaly) is a neuronal migration disorder which is associated with microdeletions in the short arm of chromosome 17. Neurofibromatosis type I (NF1) is an autosomal dominant condition associated with mutations in the long arm of chromosome 17, and characterised by neurofibromas, café-au-lait spots and axillary freckling. The neonatal period for a female infant born at 39 weeks gestation by emergency Caesarean section was complicated by frequent epileptic seizures as well as hypotonia. A computed tomography scan revealed evidence of lissencephaly, and chromosomal analysis showed a microdeletion on the short arm of chromosome 17 (17p13.3), confirming the diagnosis as Miller-Dieker syndrome. The child died at the age of 4 years and examination of the brain confirmed lissencephaly with a thickened cortex, deficient white matter, and grey matter heteropias. The mother had café-au-lait spots, and axillary freckling. In addition, the mother's and maternal grandmother's genetic analysis showed identical mutations in the neurofibromatosis I gene on the long arm of chromosome 17, confirming the diagnosis of NF1. The child did not possess the mutation. This case illustrates a rare neuronal migration disorder appearing in a child from a family with a history of NF1.

Abnormalities, Multiple↗

PubMed2004

Laterality of the aortic arch and anomalies of the subclavian artery-reliable indicators for 22q11.2 deletion syndromes?

UNLABELLED: A variety of cardiac defects, encompassing truncus arteriosus, tetralogy of Fallot, pulmonary atresia with ventricular septal defect and interrupted aortic arch, are generally summarised as conotruncal malformations. Patients with these cardiac defects were frequently found to have a common microdeletion on chromosome 22, the so-called monosomy 22q11.2. The aim of our study was to determine whether the laterality of the aortic arch or the presence of subclavian artery anomalies (SAA) represent markers for monosomy 22q11.2 in these patients. 170 patients with these cardiac anomalies were recruited at presentation in the paediatric cardiology units of two tertiary referral centres from 1994 until 2003. Of the 170 children and young adults, 33 had interrupted aortic arch, 35 tetralogy of Fallot, 31 truncus arteriosus communis and 71 pulmonary atresia with ventricular septal defect. All were screened for monosomy 22q11.2 and the results were correlated with the laterality of the aortic arch and the presence of SAA contralateral to the aortic arch (aberrant origin from the descending aorta, isolation, distal ductal origin from the pulmonary artery and cervical origin of the right subclavian artery). Monosomy 22q11.2 was present in 59/170 patients (35%). A left aortic arch (LAA) was found in 118 (69%), a right aortic arch (RAA) in 52 (31%) patients. Almost 50% of the patients with RAA (46%), but only 30% of the patients with LAA had monosomy 22q11.2 ( P=0.054). A total of 47 patients (28%) had an anomaly of the subclavian artery, 81% of whom had monosomy 22q11.2. This deletion was found in decreasing percentage in patients with LAA+SAA (85%) >RAA+SAA (75%) >RAA without SAA (28%) >LAA without SAA (13%). CONCLUSION: In patients with conotruncal malformations, anomalies of the subclavian arteries are the most important anatomical marker for the presence of monosomy 22q11.2, independent of the laterality of the aortic arch. Therefore, we recommend cytogenetic testing for this microdeletion in all patients with subclavian artery anomalies and conotruncal malformations.

Adolescent↗

PubMed2006

Mutations and novel polymorphisms in coding regions and UTRs of CDK5R1 and OMG genes in patients with non-syndromic mental retardation.

Mental retardation (MR) is displayed by 57% of NF1 patients with microdeletion syndrome as a result of 17q11.2 region haploinsufficiency. We considered the cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) and oligodendrocyte-myelin glycoprotein (OMG) genes, mapping in the NF1 microdeleted region, as candidate genes for MR susceptibility. CDK5R1 encodes for a neurone-specific activator of cyclin-dependent kinase 5 (CDK5) involved in neuronal migration during central nervous system development. OMG encodes for an inhibitor of neurite outgrowth by the binding to the Nogo-66 receptor (RTN4R). CDK5R1 and OMG genes are characterized by large 3' and 5' untranslated regions (UTRs), where we predict the presence of several transcription/translation regulatory elements. We screened 100 unrelated Italian patients affected by unspecific MR for mutations in CDK5R1 and OMG coding regions and in their 3' or 5' UTRs. Four novel mutations and two novel polymorphisms for CDK5R1 and three novel mutations for OMG were detected, including two missense changes (c.323C>T; A108V in CDK5R1 and c.1222A>G; T408A in OMG), one synonymous codon variant (c.532C>T; L178L in CDK5R1), four variants in CDK5R1 3'UTR and two changes in OMG 5'UTR. All the mutations were absent in 370 chromosomes from normal subjects. The allelic frequencies of the two novel polymorphisms in CDK5R1 3'UTR were established in both 185 normal and 100 mentally retarded subjects. Prediction of mRNA and protein secondary structures revealed that two changes lead to putative structural alterations in the mutated c.2254C>G CDK5R1 3'UTR and in OMG T408A gene product.

Adolescent↗

PubMed2004

Prenatal diagnosis of aneuploidy and deletion 22q11.2 in fetuses with ultrasound detection of cardiac defects.

OBJECTIVE: We report a prospective database evaluation of the occurrence of aneuploidy and deletion 22q11.2 after prenatal detection of cardiac abnormalities. To ensure the maximum inclusion, all cardiac defects were considered, with the exception of echogenic intracardiac foci. STUDY DESIGN: Prenatal specimens with ultrasound findings of cardiac defects were identified. Physicians were provided supplementary information that described the risk of deletion 22q11.2 syndrome if the karyotype was normal. On approval, fluorescence in situ hybridization was performed to identify the 22q11.2 microdeletion. RESULTS: Prenatal detection of cardiac abnormalities identified aneuploidy or unbalanced chromosome rearrangements in 41% of the cases that were studied. In those fetuses with normal karyotypes, 3% had the deletion 22q11.2. CONCLUSION: These results indicate that prenatal ultrasound findings of congenital heart defects identify fetuses who are at increased risk for chromosome abnormalities. Fetuses with normal karyotypes should consider having fluorescence in situ hybridization studies for the microdeletion 22q11.2 syndrome. Chromosome and fluorescence in situ hybridization studies of family members should be recommended when a fetus is identified as having the deletion 22q11.2.

Adolescent↗

PubMed2006

Mouse models of 22q11 deletion syndrome.

22q11 deletion syndrome (22q11DS) is caused by an interstitial chromosomal microdeletion that encompasses about 40 genes. It is the most common of the microdeletion syndromes. The clinical phenotype, which is complex and variable, includes specific congenital defects of the cardiovascular system, craniofacies, and immune system. In early childhood, patients manifest cognitive impairment, behavioral disorders, and delays in motor development and language acquisition. Adult patients have a high risk for developing serious psychiatric disorders, especially schizophrenia, schizoaffective disorder, and bipolar disorder. The great majority of patients have an identical or near identical chromosomal deletion, and genotype-phenotype correlations have not been established. Indeed, little progress was made toward resolving the complex clinical phenotype until the deletion was successfully modeled in the mouse. In recent years, through a variety of mouse mutants that carry multigene and single gene mutations, we have learned that mutation in a single gene, Tbx1, is responsible for most of the congenital defects seen in the mouse models and in patients. We now face a greater challenge as we attempt to use the mouse to address the pathogenesis of the behavioral and psychiatric disorders associated with 22q11DS. Significant progress has already been made, and recent studies in the mouse suggest that several genes from the deleted region affect behavior and might contribute to disease burden in patients.

Animals↗

PubMed2005

Uniparental disomy and imprinting defects in Japanese patients with Angelman syndrome.

We examined 54 patients with deletion-negative Angelman syndrome (AS) using DNA methylation testing and microsatellite polymorphism analysis, and identified three patients with paternal uniparental disomy (UPD) and seven patients with imprinting defects (ID). The three patients with UPD were shown to have paternal isodisomy 15, which we hypothesized to have arisen from duplication of chromosome 15. Two of the patients with ID were siblings and carried microdeletions of the imprinting center (IC), while the remaining five patients had no evidence of deletions and represented sporadic cases. Two of the three patients with UPD and two of the seven patients with ID had not developed seizures. The only patients displaying microcephaly were those with ID who had microdeletions at the IC. These data support the previous findings that indicate that patients with UPD and ID may have a milder phenotype of AS.

Angelman Syndrome↗

PubMed2006

Molecular cytogenetic characterization of deletions on der(9) in chronic myelocytic leukemia.

The t(9;22)(q34;q11), generating the Philadelphia chromosome, is found in more than 90% of patients with chronic myelocytic leukemia (CML). Deletions adjacent to the translocation breakpoint on the derivative chromosome 9 have been described by several groups. These studies revealed two primary points: (1) genomic microdeletions were concomitant with the t(9;22) rearrangement; and (2) the location of the deleted sequence was centromeric to ABL and telomeric to BCR genes. We report on a detailed molecular cytogenetic characterization of chromosomal rearrangements in two CML patients bearing a complex variant t(9;22) and insertions of chromosome 22 sequences in 9q34. Our study shows that the location of the deleted sequences was downstream of the ABL gene and that genomic microdeletions were concomitant with the ins(9;22)(q34;q11q11) rearrangement.

Adult↗

PubMed2005

Prader-Willi syndrome with a karyotype 47,XY,+min(15)(pter->q11.1:) and maternal UPD 15--case report plus review of similar cases.

Prader-Willi (PWS) and Angelman (AS) are syndromes of developmental impairment that can result either from a 15q11-q13 deletion, paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. A small cytogenetic subset of PWS and AS patients are carriers of a so-called small supernumerary marker chromosome (sSMC). Here, we report on an previously unreported PWS case with a karyotype 47,XY,+min(15)(pter->q11.1:) plus maternal heterodisomic UPD 15. A review of the literature revealed, that for both, PWS and AS patients, cases with (1) a sSMC plus microdeletion of the PWS/AS critical region, (2) inv dup(15) plus uniparental disomy (UPD) 15 and (3) cases without exclusion of a microdeletion an UBE3A mutation or UPD are described. The present case as well as the review of similar cases provides further evidence for the necessity to test UPD in prenatal cases with a de novo sSMC and in postnatal cases with otherwise unexplainable clinical phenotype.

Angelman Syndrome↗

PubMed2005

Role of the AZFd locus in spermatogenesis.

To determine the prevalence of Y-chromosome microdeletions among infertile men and to correlate the clinical presentation of the men with specific deletions, microdeletion analysis in 53 infertile men (30 nonobstructive azoospermic, 23 severely oligozoospermic patients), and 100 age-matched, fathered normospermic men who had fathered children was performed by the multiplex PCR with 18 different Y-chromosome-specific STS primer sets, spanning the AZFa, AZFb, AZFd, and AZFc regions. Detection of the same locus deletion of the AZFd region in three cases indicated the possible importance of the genes located in this region in spermatogenesis.

Chromosome Deletion↗

PubMed2006

[Molecular anomalies of the Y chromosome: Consequences on male fertility].

Molecular anomalies of the Y chromosome leading to male infertility are mainly microdeletions of the long arm of the Y chromosome. Three recurrently deleted portions of the long arm are the AZFa, AZFb and AZFc (AZF: Azoospermia Factor) regions. Complete deletions of the AZFc region are found in 10% of cases of severe male infertility. In addition to the AZF deletions, certain classes of Y chromosome (haplogroups) may also predispose to male infertility and could be transmitted to future male descents by various Assisted Reproductive Techniques (ART). Since the first discovery of microdeletions, the sequence of the Y chromosome has become available, revealing the mechanisms underlying deletion formation and also resulting in a coherent screening strategy. Recently, partial deletions of the AZF regions have been described. The significance of these deletions in the clinical context remains to be defined.

Biological Evolution↗

PubMed2005

Ubiquitin fusion degradation 1-like gene dysregulation in bicuspid aortic valve.

OBJECTIVE: Bicuspid aortic valve, the most common congenital cardiac malformation, is caused by fusion of valve cushions at the onset of valvulogenesis. Although its exact pathogenesis is still unclear, a genetic basis is appearing more and more likely. Search for a potential candidate gene by reviewing semilunar valve morphogenesis led us to the ubiquitin fusion degradation 1-like gene (UFD1L), which is highly expressed in the cardiac outflow tract during embryogenesis. METHODS: Aortic valves were collected during surgery from 39 patients with bicuspid aortic valve (mean age 56.8 +/- 18.1 years) and from 38 patients with tricuspid aortic valve (mean age 61.7 +/- 16.1 years). Fluorescence in situ hybridization was performed for detection of microdeletion, quantitative reverse transcriptase-polymerase chain reaction to measure gene expression, and Western blotting to analyze the amount of UFD1L gene product. RESULTS: No microdeletion was found in either group in the critical region of chromosome 22 containing the UFD1L gene. UFD1L gene expression, however, was significantly reduced in bicuspid aortic valve samples (median 787-fold) relative to tricuspid aortic valve samples (median 10,887-fold, P = .001). The amount of UFD1L gene product was also significantly diminished in bicuspid aortic valve samples (3.9 +/- 2.6 vs 8.4 +/- 4.8 optical density units, P < .05). CONCLUSION: Bicuspid aortic valve was associated with downregulation of UFD1L gene expression, supporting the hypothesis that bicuspid aortic valve is a genetic disorder, with the UFD1L gene as a potential candidate gene.

Adaptor Proteins, Vesicular Transport↗