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PubMedDate not supplied

[Infertility caused by AZF microdeletions. A new case of azoospermia].

We report report a case of a man with azoospermia who was studied because of infertility. Between the causes of azoospermia and severe oligospermia, in male patients with infertility evaluations, small deletions in regions of the Y chromosome must be considered, as in our case. Regions for spermatogenesis in the Yq chromosome can be evidenced using PCR analysis. Men with azoospermia are at high risk to have small deletions in that regions. Yq chromosome deletions could be transmitted when ICSI (intracytoplasmic sperm injection) is applied. Thereafter, study of microdeletions would be included in severe infertile men.

Adult↗
PubMed2000

Ventricular septal defect associated with microdeletions of chromosome 22q11.2.

Microdeletions of chromosome 22q11.2 (del.22q11) cause DiGeorge syndrome, velo-cardio-facial syndrome, and conotruncal anomaly face syndrome, which are commonly associated with conotruncal heart anomalies. Approximately 15% of the patients manifest ventricular septal defect (VSD), and the conal septal type of VSD has been proposed to be associated with del.22q11, since it is categorized as a conotruncal anomaly. However, the types of VSD associated with del.22q11 remain poorly studied. The purpose of this study is to assess whether conal septal VSD or other types of VSDs are associated with del.22q11. We analyzed the chromosomes of 22 consecutive patients with conal-septal VSD, prospectively, and evaluated the types of VSD observed in 3 patients with del.22q11, retrospectively. Del.22q11 was not detected in any of the 22 patients with conal septal VSD. All the VSDs observed in the 3 patients with del.22q11 were a perimembranous type of VSD, which is not a conotruncal anomaly. Our results suggest that perimembranous VSD can be associated with del.22q11, but del.22q11 is not a common cause of conal-septal VSD.

Adolescent↗
PubMed2001

Familial case of Potocki-Shaffer syndrome associated with microdeletion of EXT2 and ALX4.

Multiple exostosis, biparietal foramina, minor craniofacial abnormalities, and mental retardation are characteristic of the syndrome associated with a proximal deletion of 11p (MIM # 601224), which has been shown to be a true contiguous gene deletion syndrome. The presence of multiple exostosis is associated with deletion of the EXT2 gene. Similarly, the presence of biparietal foramina has been shown to be associated with the deletion of ALX4 located proximally to EXT2. Specific genes related to mental retardation and craniofacial abnormalities, however, have yet to be identified. We report on a family with a microdeletion of 11(pll.2p11.2) with multiple exostosis and biparietal foramina without mental retardation or craniofacial abnormalities. Our results suggest that genes related to mental retardation and craniofacial development must be located outside of the D11S1785-D11S1385 region.

Child↗
PubMed1995

Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15.

A subset of patients with Angelman and Prader-Willi syndrome have apparently normal chromosomes of biparental origin, but abnormal DNA methylation at several loci within chromosome 15q11-13, and probably have a defect in imprinting. Using probes from a newly established 160-kb contig including D15S63 (PW71) and SNRPN, we have identified inherited microdeletions in two AS families and three PWS families. The deletions probably affect a single genetic element that we term the 15q11-13 imprinting centre (IC). In our model, the IC regulates the chromatin structure, DNA methylation and gene expression in cis throughout 15q11-13. Mutations of the imprinting centre can be transmitted silently through the germline of one sex, but appear to block the resetting of the imprint in the germline of the opposite sex.

Angelman Syndrome↗
PubMed1996

A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria.

We have identified a 15-bp microdeletion in a highly conserved region of the mitochondrially encoded gene for cytochrome c oxidase (COX) subunit III in a patient with severe isolated COX deficiency and recurrent myoglobinuria. The mutant mitochondrial DNA (mtDNA) comprised 92% of the mtDNA in muscle and 0.7% in leukocytes. Immunoblots and immunocytochemistry suggested a lack of assembly or instability of the complex. Microdissected muscle fibres revealed significantly higher portions of mutant mtDNA in COX-negative than in COX-positive fibres. This represents the first case of isolated COX deficiency to be defined at the molecular level.

Adolescent↗
PubMed2004

Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome.

The overgrowth- and tumor-associated Beckwith-Wiedemann syndrome results from dysregulation of imprinted genes on chromosome 11p15.5. Here we show that inherited microdeletions in the H19 differentially methylated region (DMR) that abolish two CTCF target sites cause this disease. Maternal transmission of the deletions results in hypermethylation of the H19 DMR, biallelic IGF2 expression, H19 silencing and Beckwith-Wiedemann syndrome, indicative of loss of function of the IGF2-H19 imprinting control element.

Alleles↗
PubMed2006

A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism.

Submicroscopic genomic copy number changes have been identified only recently as an important cause of mental retardation. We describe the detection of three interstitial, overlapping 17q21.31 microdeletions in a cohort of 1,200 mentally retarded individuals associated with a clearly recognizable clinical phenotype of mental retardation, hypotonia and a characteristic face. The deletions encompass the MAPT and CRHR1 genes and are associated with a common inversion polymorphism.

Adolescent↗
PubMed2006

Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability.

Recently, the application of array-based comparative genomic hybridization (array CGH) has improved rates of detection of chromosomal imbalances in individuals with mental retardation and dysmorphic features. Here, we describe three individuals with learning disability and a heterozygous deletion at chromosome 17q21.3, detected in each case by array CGH. FISH analysis demonstrated that the deletions occurred as de novo events in each individual and were between 500 kb and 650 kb in size. A recently described 900-kb inversion that suppresses recombination between ancestral H1 and H2 haplotypes encompasses the deletion. We show that, in each trio, the parent of origin of the deleted chromosome 17 carries at least one H2 chromosome. This region of 17q21.3 shows complex genomic architecture with well-described low-copy repeats (LCRs). The orientation of LCRs flanking the deleted segment in inversion heterozygotes is likely to facilitate the generation of this microdeletion by means of non-allelic homologous recombination.

Adolescent↗
PubMed2006

Conservation of hotspots for recombination in low-copy repeats associated with the NF1 microdeletion.

Several large-scale studies of human genetic variation have provided insights into processes such as recombination that have shaped human diversity. However, regions such as low-copy repeats (LCRs) have proven difficult to characterize, hindering efforts to understand the processes operating in these regions. We present a detailed study of genetic variation and underlying recombination processes in two copies of an LCR (NF1REPa and NF1REPc) on chromosome 17 involved in the generation of NF1 microdeletions and in a third copy (REP19) on chromosome 19 from which the others originated over 6.7 million years ago. We find evidence for shared hotspots of recombination among the LCRs. REP19 seems to contain hotspots in the same place as the nonallelic recombination hotspots in NF1REPa and NF1REPc. This apparent conservation of patterns of recombination hotspots in moderately diverged paralogous regions contrasts with recent evidence that these patterns are not conserved in less-diverged orthologous regions of chimpanzees.

Animals↗
PubMed2006

Interstitial 9q22.3 microdeletion: clinical and molecular characterisation of a newly recognised overgrowth syndrome.

In the course of a systematic whole genome screening of patients with unexplained overgrowth syndrome by microarray-based comparative genomic hybridisation (array-CGH), we have identified two children with nearly identical 6.5 Mb-long de novo interstitial deletions at 9q22.32-q22.33. The clinical phenotype includes macrocephaly, overgrowth and trigonocephaly. In addition, both children present with psychomotor delay, hyperactivity and distinctive facial features. Further analysis with a high-resolution custom microarray covering the whole breakpoint intervals with fosmids mapped the deletion breakpoints within 100-kb intervals: although the deletion boundaries are different for the two patients, nearly the same genes are deleted in both cases. We suggest therefore that microdeletion of 9q22.32-q22.33 is a novel cause of overgrowth and mental retardation. Its association with distinctive facial features should help in recognising this novel phenotype.

Child, Preschool↗
PubMed2006

Parental and chromosomal origins of microdeletion and duplication syndromes involving 7q11.23, 15q11-q13 and 22q11.

Non-allelic homologous recombination between chromosome-specific LCRs is the most common mechanism leading to recurrent microdeletions and duplications. To look for locus-specific differences, we have used microsatellites to determine the parental and chromosomal origins of a large series of patients with de novo deletions of chromosome 7q11.23 (Williams syndrome), 15q11-q13 (Angelman syndrome, Prader-Willi syndrome) and 22q11 (Di George syndrome) and duplications of 15q11-q13. Overall the majority of rearrangements were interchromosomal, so arising from unequal meiotic exchange, and there were approximately equal numbers of maternal and paternal deletions. Duplications and deletions of 15q11-q13 appear to be reciprocal products that arise by the same mechanisms. The proportion arising from interchromosomal exchanges varied among deletions with 22q11 the highest and 15q11-q13 the lowest. However, parental and chromosomal origins were not always independent. For 15q11-q13, maternal deletions tended to be interchromosomal while paternal deletions tended to be intrachromosomal; for 22q11 there was a possible excess of maternal cases among intrachromosomal deletions. Several factors are likely to be involved in the formation of recurrent rearrangements and the relative importance of these appear to be locus-specific.

Angelman Syndrome↗
PubMed2004

Susceptibility gene for non-obstructive azoospermia in the HLA class II region: correlations with Y chromosome microdeletion and spermatogenesis.

We previously reported an association between the human leukocyte antigen (HLA) haplotype DRB1*1302-DQB1*0604 in the HLA class II region and non-obstructive azoospermia in Japanese men. To identify possible associations between the HLA-DRB1*1302-DQB1*0604 allele in the HLA class II region and azoospermia factor (AZF) deletion in the Y chromosome, we performed genomic polymerase chain reaction (PCR) analysis of the AZF region. We then determined spermatogenic impairment (Johnsen score) in testicular biopsy specimens from patients with or without the DRB1*1302-DQB1*0604 haplotype. The AZF microdeletion rate in patients with this haplotype was 3.85%, compared with 11.8% in others (no correlation). However, Johnsen scores in patients with the DRB1*1302-DQB1*0604 haplotype were 3.13 +/- 1.34 (mean +/- SD), compared with 3.70 +/- 1.51 in others (p < 0.05). While the DRB1*1302-DQB1*0604 haplotype acts independently from Y chromosome deletion, the haplotype might either act directly, or be functionally related to an unknown autosomal gene. In either case, this haplotype showed association with severe spermatogenic impairment.

Chromosome Deletion↗
PubMed1998

Prenatal diagnosis of 22q11 microdeletion in a fetus with a conotruncal heart defect.

A case of prenatal diagnosis of 22q11 microdeletion in a fetus with a conotruncal heart defect is described. This type of chromosomal aberration has been shown to be present in up to 30% of isolated conotruncal anomalies and in most cases of DiGeorge and velocardiofacial syndromes. The implications of such a diagnosis on prenatal counselling are discussed.

Amniocentesis↗
PubMed2002

Prenatal diagnosis of 22q11 microdeletion in an early second-trimester fetus with conotruncal anomaly presenting with increased nuchal translucency and bilateral intracardiac echogenic foci.

We report on a 16-week fetus, in which detection of increased nuchal translucency thickness and bilateral intracardiac echogenic foci led to the prenatal diagnosis of truncus arteriosus communis, interruption of the aortic arch and aplastic thymus. Cytogenetic examination confirmed a 22q11.2 microdeletion consistent with the suspected CATCH 22 syndrome. Subsequently hydrops fetalis developed and the fetus died in utero at 18 weeks. This case report supports the hypothesis that both cardiac failure and left ventricular outflow tract obstruction may cause increased nuchal translucency thickness. The association between increased nuchal translucency thickness and CATCH 22 syndrome should be considered in diagnostic procedures. The sonographic diagnosis of both increased nuchal translucency thickness and intracardiac echogenic foci requires specialist ultrasonography and echocardiography. In particular, identification of right-sided or bilateral echogenic foci should prompt further detailed examination.

Abnormalities, Multiple↗
PubMed2003

Comparison between direct clinical and digital photogrammetric measurements in patients with 22q11 microdeletion.

Thanks to recent advances in imaging and computing technology, photoanthropometry has become an increasingly helpful adjunct to obtain objective clinical evidence of morphologic abnormalities in patients with dysmorphic syndromes. The aim of this study was to evaluate measurements made using a new two-dimensional digital photogrammetry technique by comparison with direct clinical measurements. A total of 14 patients with 22q11 microdeletion were included in this study. There were seven females and seven males between 5 and 38 years of age. Sixteen direct clinical measurements were performed using a graduated anthropometric sliding caliper and angle meter. Photogrammetric measurements were made on digital photographs using a commercially available software package. After calibration to one in situ reference on frontal and profile views, photogrammetric measurements were compared to a total of 14 direct clinical measurements made in the same patients. Findings showed that photogrammetric measurements calibrated to an in situ reference were reliable especially on profile views. No statistical difference was found between 10 of the 14 measurements (P> 0.05) including eight of the nine measurements on profile views and two of the five measurements on frontal views. This study indicates that digital photogrammetry is a useful tool but there is still no reliable standard photographic measurement technique.

Adolescent↗
PubMed1995

Pleiotropy in microdeletion syndromes: neurologic and spermatogenic abnormalities in mice homozygous for the p6H deletion are likely due to dysfunction of a single gene.

Variability and complexity of phenotypes observed in microdeletion syndromes can be due to deletion of a single gene whose product participates in several aspects of development or can be due to the deletion of a number of tightly linked genes, each adding its own effect to the syndrome. The p6H deletion in mouse chromosome 7 presents a good model with which to address this question of multigene vs. single-gene pleiotropy. Mice homozygous for the p6H deletion are diluted in pigmentation, are smaller than their littermates, and manifest a nervous jerky-gait phenotype. Male homozygotes are sterile and exhibit profound abnormalities in spermiogenesis. By using N-ethyl-N-nitrosourea (EtNU) mutagenesis and a breeding protocol designed to recover recessive mutations expressed hemizygously opposite a large p-locus deletion, we have generated three noncomplementing mutations that map to the p6H deletion. Each of these EtNU-induced mutations has adverse effects on the size, nervous behavior, and progression of spermiogenesis that characterize p6H deletion homozygotes. Because EtNU is thought to induce primarily intragenic (point) mutations in mouse stem-cell spermatogonia, we propose that the trio of phenotypes (runtiness, nervous jerky gait, and male sterility) expressed in p6H deletion homozygotes is the result of deletion of a single highly pleiotropic gene. We also predict that a homologous single locus, quite possibly tightly linked and distal to the D15S12 (P) locus in human chromosome 15q11-q13, may be associated with similar developmental abnormalities in humans.

Animals↗
PubMedDate not supplied

Y chromosome microdeletion in a case with Klinefelter's Syndrome.

In male infertility, the frequency of genetic factors is high. Klinefelter's Syndrome is the most frequent sex chromosomal abnormality detected in male infertility. In this study we report a patient diagnosed with Klinefelter's Syndrome with a deletion of the Yq interval. The patient was 24-years old with primary infertility. Semen analyses carried out in triplicate indicated azoospermia. The plasma leutenizing hormone (LH) and follicle stimulating hormone (FSH) levels were abnormally high and the testosterone level was lower than the usual range. Each of his testes had a volume of 3 cc. Peripheral blood karyotype analysis showed Klinefelter's Syndrome (47, XXY) pattern. Polymerase chain reaction amplification of DNA was performed using the following primers; AZFa (sY81, sY82, sY84), AZFb (sY127, sY142, sY164, RBM1), AZFc (CDY, BPY, sY254, sY255, sY277), AZFd (sY152, sY145, sY153). Analysis revealed a single deletion of AZFa region (sY84). Deletion of the AZFa region may be an additional factor for absolute azoospermia in men with Klinefelter's Syndrome. For individuals with Klinefelter's Syndrome who plan to undergo assisted reproduction techniques, Y chromosome microdeletion screening can diagnostically be convenient.

Adult↗
PubMed1998

A comprehensive screen for TWIST mutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7p21.1.

Mutations in the coding region of the TWIST gene (encoding a basic helix-loop-helix transcription factor) have been identified in some cases of Saethre-Chotzen syndrome. Haploinsufficiency appears to be the pathogenic mechanism involved. To investigate the possibility that complete deletions of the TWIST gene also contribute to this disorder, we have developed a comprehensive strategy to screen for coding-region mutations and for complete gene deletions. Heterozygous TWIST mutations were identified in 8 of 10 patients with Saethre-Chotzen syndrome and in 2 of 43 craniosynostosis patients with no clear diagnosis. In addition to six coding-region mutations, our strategy revealed four complete TWIST deletions, only one of which associated with a translocation was suspected on the basis of conventional cytogenetic analysis. This case and two interstitial deletions were detectable by analysis of polymorphic microsatellite loci, including a novel (CA)n locus 7.9 kb away from TWIST, combined with FISH; these deletions ranged in size from 3.5 Mb to >11.6 Mb. The remaining, much smaller deletion was detected by Southern blot analysis and removed 2,924 bp, with a 2-bp orphan sequence at the breakpoint. Significant learning difficulties were present in the three patients with megabase-sized deletions, which suggests that haploinsufficiency of genes neighboring TWIST contributes to developmental delay. Our results identify a new microdeletion disorder that maps to chromosome band 7p21.1 and that causes a significant proportion of Saethre-Chotzen syndrome.

Acrocephalosyndactylia↗