Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Microdeletion”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 703 records · Page 39Linked to original sources
PubMed2025

Recurrent structural variation and recent turnover at the 17q21.31 locus in humans and great apes.

The 17q21.31 locus in humans harbors several complex structural haplotypes including a ~970kb inversion. Different inversion haplotypes have been associated with susceptibility to microdeletions causing Koolen-de Vries syndrome and variation in fecundity and recombination rates. Here, using 210 haplotype-resolved human genome assemblies and pangenome graph-based approaches we characterize 11 distinct structural haplotypes, several of which have not been previously described. Extending our analyses to a set of haplotype-resolved great-ape genomes, we characterize the structure of an independent inversion in chimpanzees which extends an additional 650kb, encompasses 5 additional genes, and is ~2 million years younger than the human inversion. We further determine that gorillas exhibit an independent duplication of the KANSL1 gene which may predispose them to Koolen-de Vries syndrome causing microdeletions. Using short read sequencing data we characterize 17q21.31 haplotype diversity worldwide in ~5174 individuals from 107 populations finding increased frequencies of KANSL1 duplication-containing haplotypes in both European and South Asian populations as well as 8 double recombination events between inverted and non-inverted haplotypes ranging in size from 20-180kb. Finally, using 626 ancient Eurasian human genomes we show the frequency of haplotypes containing KANSL1 duplications has increased ~6-fold over the past 12 thousand years in Europe. Together, our results highlight the dynamics, complexity, and recurrent, independent evolution of a medically relevant locus across humans and great apes.

Journal Article↗
PubMed2026

MRE11 suppresses germline mutagenesis at meiotic double-strand breaks in mice.

SPO11 forms hundreds of double-strand breaks (DSBs) to initiate meiotic recombination that is normally error-free. However, SPO11 activity can be mutagenic when one chromatid incurs closely spaced DSBs (double cuts), especially when DSBs are dysregulated by loss of the ATM kinase. De novo indels and structural variants can arise via end joining at double cuts within a single hotspot (microdeletions) or at adjacent hotspots separated by at least 30 kb, as we now show, sometimes accompanied by ectopic insertions of double-cut fragments. Here, we investigate how meiotic DSB end processing influences end joining. In MRE11-deficient mouse spermatocytes, which do not resect their DSBs, deletions at double cuts occur readily, with end-joining breakpoint profiles closely matching SPO11 DSB profiles. Microdeletions suggest that two DSBs can be as close as ∼21 bp. The tyrosyl-DNA phosphodiesterase TDP2 contributes to both deletion formation and ectopic insertion of double-cut fragments, presumably by removing SPO11 from DNA ends prior to joining. Finally, observations suggest a cooperative role for MRE11 and ATM in locally regulating DSB distributions. Our findings provide insight into the mechanism of de novo mutation origin, emphasizing the role of meiotic DSBs in shaping genome evolution.

Animals↗
PubMed1997

Genomic organization of the murine Miller-Dieker/lissencephaly region: conservation of linkage with the human region.

Several human syndromes are associated with haploinsufficiency of chromosomal regions secondary to microdeletions. Isolated lissencephaly sequence (ILS), a human developmental disease characterized by a smooth cerebral surface (classical lissencephaly) and microscopic evidence of incomplete neuronal migration, is often associated with small deletions or translocations at chromosome 17p13.3. Miller-Dieker syndrome (MDS) is associated with larger deletions of 17p13.3 and consists of classical lissencephaly with additional phenotypes including facial abnormalities. We have isolated the murine homologs of three genes located inside and outside the MDS region: Lis1, Mnt/Rox, and 14-3-3 epsilon. These genes are all located on mouse chromosome 11B2, as determined by metaphase FISH, and the relative order and approximate gene distance was determined by interphase FISH analysis. The transcriptional orientation and intergenic distance of Lis1 and Mnt/Rox were ascertained by fragmentation analysis of a mouse yeast artificial chromosome containing both genes. To determine the distance and orientation of 14-3-3 epsilon with respect to Lis1 and Mnt/Rox, we introduced a super-rare cutter site (VDE) that is unique in the mouse genome into 14-3-3 epsilon by gene targeting. Using the introduced VDE site, the orientation of this gene was determined by pulsed field gel electrophoresis and Southern blot analysis. Our results demonstrate that the MDS region is conserved between human and mouse. This conservation of linkage suggests that the mouse can be used to model microdeletions that occur in ILS and MDS.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1986

Tricho-rhino-phalangeal syndrome without exostoses, wih an interstitial deletion of 8q23.

We report on a patient with the Tricho-Rhino-Phalangeal syndrome (TRPS) with normal mentation, without exostoses and with a partial microdeletion of 8q23. Although she had the phenotypic characteristics of TRPS Type I, karyotypic analysis demonstrated the 8q-microdeletion usually associated with TRPS Type II, in which exostoses are present. Our patient represents the second reported instance of this phenotypic chromosomal association and provides further evidence for homogeneity of the TRPS.

Abnormalities, Multiple↗
PubMed1997

Chromosome deletion 17p11.2 (Smith-Magenis syndrome) in seven new patients, four of whom had been referred for fragile-X investigation.

We report seven new patients with clinical features of the Smith-Magenis syndrome (SMS) and small de novo interstitial deletions of 17p11.2. Four of these patients had been referred for fragile-X studies, but standard G-banded chromosome analysis routinely carried out in addition to the fragility tests revealed the microdeletion in chromosome 17. A relatively high proportion (approximately 2%) of patients referred to this Centre for fragile-X investigation are found to have a chromosome abnormality other than fra(X)(q27.3), half of them (approximately 1%) with an unbalanced chromosome complement. The four of our seven patients with deletion 17p11.2 constitute 25% of those with an unbalanced karyotype, and establish this microdeletion as the most common chromosome abnormality-except for fra(X)(q27.3)-in patients referred for fragile-X screening. The data indicate that standard karyotyping should be offered to patients with this referral indication, in addition to any molecular or chromosome fragility tests for fragile X. We also recommend that the short arm of chromosome 17 be examined critically in these patients. Moderate quality and resolution of banding (450-550 bands per haploid chromosome set) are adequate for detection of the 17p11.2 deletion.

Abnormalities, Multiple↗
PubMed2002

INK4a-ARF alterations in liver cell adenoma.

BACKGROUND: The INK4a-ARF (CDKN2A) locus on chromosome 9p21 encodes two tumour suppressor proteins, p16(INK4a) and p14(ARF), whose functions are inactivated in many human cancers. AIMS: To evaluate p14(ARF) and p16(INK4a) alterations in liver cell adenoma. METHODS: After microdissection, DNA from 25 liver cell adenomas and corresponding normal liver tissue were analysed for INK4-ARF inactivation by DNA sequence analysis, methylation specific polymerase chain reaction, 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. RESULTS: Methylation of p14(ARF) was found in 3/25 cases (12%) and alterations in p16(INK4a) occurred in 6/25 liver cell adenomas (24%) which correlated with loss of mRNA transcription. We failed to detect microdeletions or specific mutations of both exons. p16(INK4a) methylation appeared in the context of an unmethylated p14(ARF) promoter in six cases. In normal liver tissue, p14(ARF) or p16(INK4a) alterations were not observed. CONCLUSIONS: Our data suggest that p14(ARF) methylation occurs independently of p16(INK4a) alterations in liver cell adenomas. Furthermore, methylation of p14(ARF) and p16(INK4a) may be a result of cell cycle deregulation and does not seem to be a prerequisite of malignancy.

Adenoma, Liver Cell↗
PubMed2005

Prenatal detection of unbalanced chromosomal rearrangements by array CGH.

BACKGROUND: Karyotype analysis has been the standard method for prenatal cytogenetic diagnosis since the 1970s. Although highly reliable, the major limitation remains the requirement for cell culture, resulting in a delay of as much as 14 days to obtaining test results. Fluorescent in situ hybridisation (FISH) and quantitative fluorescent PCR (QF-PCR) rapidly detect common chromosomal abnormalities but do not provide a genome wide screen for unexpected imbalances. Array comparative genomic hybridisation (CGH) has the potential to combine the speed of DNA analysis with a large capacity to scan for genomic abnormalities. We have developed a genomic microarray of approximately 600 large insert clones designed to detect aneuploidy, known microdeletion syndromes, and large unbalanced chromosomal rearrangements. METHODS: This array was tested alongside an array with an approximate resolution of 1 Mb in a blind study of 30 cultured prenatal and postnatal samples with microscopically confirmed unbalanced rearrangements. RESULTS: At 1 Mb resolution, 22/30 rearrangements were identified, whereas 29/30 aberrations were detected using the custom designed array, owing to the inclusion of specifically chosen clones to give increased resolution at genomic loci clinically implicated in known microdeletion syndromes. Both arrays failed to identify a triploid karyotype. Thirty normal control samples produced no false positive results. CONCLUSIONS: Analysis of 30 uncultured prenatal samples showed that array CGH is capable of detecting aneuploidy in DNA isolated from as little as 1 ml of uncultured amniotic fluid; 29/30 samples were correctly diagnosed, the exception being another case of triploidy. These studies demonstrate the potential for array CGH to replace conventional cytogenetics in the great majority of prenatal diagnosis cases.

Chromosome Aberrations↗
PubMed1994

Anophthalmia with cleft palate and micrognathia: a new syndrome?

A 5 day old male with bilateral anophthalmos, hypospadias, bifid scrotum, micrognathia, and cleft palate with normal chromosomes is described. There have been two case reports with similar clinical manifestations but associated with interstitial deletion of 14q (q22q23). We propose that either our patient represents a new syndrome or has a microdeletion which could not be detected on routine cytogenetics. High quality cytogenetics and FISH may show microdeletions in patients presenting with this clinical picture and normal chromosomes.

Abnormalities, Multiple↗
PubMed2006

High-resolution analysis of chromosomal breakpoints and genomic instability identifies PTPRD as a candidate tumor suppressor gene in neuroblastoma.

Although neuroblastoma is characterized by numerous recurrent, large-scale chromosomal imbalances, the genes targeted by such imbalances have remained elusive. We have applied whole-genome oligonucleotide array comparative genomic hybridization (median probe spacing 6 kb) to 56 neuroblastoma tumors and cell lines to identify genes involved with disease pathogenesis. This set of tumors was selected for having either 11q loss or MYCN amplification, abnormalities that define the two most common genetic subtypes of metastatic neuroblastoma. Our analyses have permitted us to map large-scale chromosomal imbalances and high-level amplifications at exon-level resolution and to identify novel microdeletions and duplications. Chromosomal breakpoints (n = 467) generating imbalances >2 Mb were mapped to intervals ranging between 6 and 50 kb in size, providing substantial information on each abnormality. For example, breakpoints leading to large-scale hemizygous loss of chromosome 11q were highly clustered and preferentially associated with segmental duplications. High-level amplifications of MYCN were extremely complex, often resulting in a series of discontinuous regions of amplification. Imbalances (n = 540) <2 Mb long were also detected. Although the majority (78%) of these imbalances mapped to segmentally duplicated regions and primarily reflect constitutional copy number polymorphisms, many subtle imbalances were detected that are likely somatically acquired alterations and include genes involved with tumorigenesis, apoptosis, or neural cell differentiation. The most frequent microdeletion involved the PTPRD locus, indicating a possible tumor suppressor function for this gene.

Cell Line, Tumor↗
PubMed2004

Molecular basis of Sotos syndrome.

This paper describes the isolation of a novel human gene, NSD1, from the 5q35 breakpoint of t(5;8)(q35; q24.1) in a patient with Sotos syndrome, and NSD1 mutation analysis. Of 112 (95 Japanese and 17 non-Japanese) patients analyzed, 16 (14%) had a heterozygous NSD1 point mutation (10 protein truncation types and six missense types) and 50 (45%) a approximately 0.7-Mb microdeletion involving NSD1. The results indicated that haploinsufficiency of NSD1 is the major cause of Sotos syndrome, and NSD1 plays a role in growth and brain development in humans. Detailed clinical examinations provided a genotype-phenotype correlation in Sotos syndrome, i.e. in patients with deletions, overgrowth is less obvious and mental retardation is more severe than in those with point mutations, and major anomalies were exclusively seen in the former. The results also indicated that Sotos syndrome due to a deletion falls into a contiguous gene syndrome, while Sotos syndrome due to an NSD1 point mutation is a single gene defect, occasionally with an autosomal dominant mode of inheritance. The genomic structure around the deleted and flanking regions revealed the presence of two sets of low copy repeats through which the microdeletion in Sotos syndrome is mediated.

Brain↗
PubMed2005

Chromosome abnormalities in sperm of individuals with constitutional sex chromosomal abnormalities.

The most common type of karyotype abnormality detected in infertile subjects is represented by Klinefelter's syndrome, and the most frequent non-chromosomal alteration is represented by Y chromosome long arm microdeletions. Here we report our experience and a review of the literature on sperm sex chromosome aneuploidies in these two conditions. Non mosaic 47,XXY Klinefelter patients (12 subjects) show a significantly lower percentage of normal Y-bearing sperm and slightly higher percentage of normal X-bearing sperm. Consistent with the hypothesis that 47,XXY germ cells may undergo and complete meiosis, aneuploidy rate for XX- and XY-disomies is also increased with respect to controls, whereas the percentage of YY-disomies is normal. Aneuploidy rates in men with mosaic 47,XXY/46,XY (11 subjects) are lower than those observed in men with non-mosaic Klinefelter's syndrome, and only the frequency of XY-disomic sperm is significantly higher with respect to controls. Although the great majority of children born by intracytoplasmic sperm injection from Klinefelter subjects are chromosomally normal, the risk of producing offspring with chromosome aneuploidies is significant. Men with Y chromosome microdeletions (14 subjects) showed a reduction of normal Y-bearing sperm, and an increase in nullisomic and XY-disomic sperm, suggesting an instability of the deleted Y chromosome causing its loss in germ cells, and meiotic alterations leading to XY non-disjunction. Intracytoplasmic injection of sperm from Y-deleted men will therefore transmit the deletion to male children, and therefore the spermatogenic impairment, but raises also concerns of generating 45,X and 47,XXY embryos.

Chromosome Aberrations↗
PubMedDate not supplied

Lack of loss of heterozygosity at the c-erbA beta locus in gastrointestinal tumors.

The cellular homologues of the viral oncogene c-erbA encode for the nuclear thyroid hormone receptor c-erbA (TR). The gene for the human TR beta subtype is located on chromosome 3p24, and a loss of heterozygosity around this region has been reported in breast and small cell lung cancers, suggesting that TR beta might act as a tumor suppressor gene. In the present study, we used PCR-based restriction fragment length polymorphisms to examine the 3p24 region of 19 patients with gastrointestinal tumors for loss of heterozygosity (LOH). Interestingly, only 1 of the patients had an LOH at this locus, while 4 patients had a microdeletion of both alleles in the 3p24 region. These results suggest that, in contrast to previous reports on lung and breast cancers, a loss of heterozygosity of the TR locus at 3p24 is a rare event. A critical review of the literature, however, suggests, that some of the earlier studies have used markers whose location is only imprecisely mapped and may hence point to a tumor suppressor gene candidate other than TR beta. However, a selective microdeletion of both alleles was detected in the tumors of 4 of the 19 patients, indicating that this region on chromosome 3p may be genetically unstable in gastrointestinal tumors.

Aged↗
PubMed1989

Molecular analysis of a female Lesch-Nyhan patient.

We report the identification of a female patient with the X-linked recessive Lesch-Nyhan syndrome (hypoxanthine phosphoribosyltransferase [HPRT] deficiency). Cytogenetic and carrier studies revealed structurally normal chromosomes for this patient and her parents and demonstrated that this mutation arose through a de novo gametic event. Comparison of this patient's DNA with the DNA of her parents revealed that a microdeletion, which occurred within a maternal gamete and involved the entire HPRT gene, was partially responsible for the disease in this patient. Somatic cell hybrids, generated to separate maternal and paternal X chromosomes, showed that expression of two additional X-linked enzymes, phosphoglycerate kinase and glucose-6-phosphate dehydrogenase, were expressed only in cells that contained the maternal X chromosome, suggesting the presence of a functionally inactive paternal X chromosome. Furthermore, comparison of methylation patterns within a region of the HPRT gene known to be important in gene regulation revealed differences between DNA from the father and the patient, in keeping with an active HPRT locus in the father and an inactive HPRT locus in the patient. Together these data indicate that nonrandom inactivation of the cytogenetically normal paternal X chromosome and a microdeletion of the HPRT gene on an active maternal X chromosome were responsible for the absence of HPRT in this patient.

Blotting, Southern↗
PubMed2005

Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome.

Williams syndrome (WS), caused by microdeletion of some 21 genes on chromosome 7q11.23, is characterized by dysmorphic features, mental retardation or learning difficulties, elastin arteriopathy, and striking neurocognitive and social-behavioral abnormalities. Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (HF). Furthermore, deficits in spatial navigation and long-term memory, major cognitive domains dependent on hippocampal function, have been described in WS. We used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 participants with WS and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior HF in WS. Spectroscopic measures of N-acetyl aspartate, considered a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. These data demonstrate abnormalities in HF in WS in agreement with murine models, implicate LIMK1 and CYLN2 in human hippocampal function, and suggest that hippocampal dysfunction may contribute to neurocognitive abnormalities in WS.

Adult↗
PubMed1999

Systematic mutation analysis of the catechol O-methyltransferase gene as a candidate gene for schizophrenia.

OBJECTIVE: Catechol O-methyltransferase (COMT) is involved in the degradation of catecholamine neurotransmitters. Recent linkage studies of schizophrenia and molecular studies of velocardiofacial syndrome suggest that the COMT gene might be a candidate gene for schizophrenia. METHOD: The authors systematically searched for mutations and microdeletion of the COMT gene in 177 Chinese schizophrenic patients from Taiwan; 99 comparison subjects were also studied. RESULTS: Five molecular variants were identified: c.186C > T at exon 3, c.408C > G at exon 4, c.472G > A at exon 4, c.597G > A at exon 5, and c.821-827insC at the 3' untranslated region. However, no differences in the genotype and haplotype frequencies of these molecular variants between the schizophrenic and comparison subjects were detected. Furthermore, no microdeletion was identified among the patients. CONCLUSIONS: These data suggest that the COMT gene does not play a major role in the pathogenesis of schizophrenia, and the genotypic overlap between schizophrenia and velocardiofacial syndrome was rare in this cohort.

Catechol O-Methyltransferase↗
PubMed1994

Isolated glycerol kinase deficiency in a neonate.

Glycerol kinase deficiency occurs either as a relatively benign isolated enzyme deficiency, or as part of a syndrome resulting from a microdeletion in the p21 region of the X chromosome associated with congenital adrenal hypoplasia and/or Duchenne muscular dystrophy. Developmental delay is a consistent feature of the microdeletion syndrome but not of the isolated enzyme defect. We report a case of isolated glycerol kinase deficiency in a neonate presenting with hypotonia, apnea, mild developmental delay, and glyceroluria, without evidence of adrenal insufficiency or myopathy. A mild communicating hydrocephalus was noted on magnetic resonance imaging brain scan. It is important, therefore, to exclude glyceroluria in infants being investigated for apnea and hypotonia.

Apnea↗
PubMed2006

Large scale copy number variation (CNV) at 14q12 is associated with the presence of genomic abnormalities in neoplasia.

BACKGROUND: Advances made in the area of microarray comparative genomic hybridization (aCGH) have enabled the interrogation of the entire genome at a previously unattainable resolution. This has lead to the discovery of a novel class of alternative entities called large-scale copy number variations (CNVs). These CNVs are often found in regions of closely linked sequence homology called duplicons that are thought to facilitate genomic rearrangements in some classes of neoplasia. Recently, it was proposed that duplicons located near the recurrent translocation break points on chromosomes 9 and 22 in chronic myeloid leukemia (CML) may facilitate this tumor-specific translocation. Furthermore, approximately 15-20% of CML patients also carry a microdeletion on the derivative 9 chromosome (der(9)) and these patients have a poor prognosis. It has been hypothesised that der(9) deletion patients have increased levels of chromosomal instability. RESULTS: In this study aCGH was performed and identified a CNV (RP11-125A5, hereafter called CNV14q12) that was present as a genomic gain or loss in 10% of control DNA samples derived from cytogenetically normal individuals. CNV14q12 was the same clone identified by Iafrate et al. as a CNV. Real-time polymerase chain reaction (Q-PCR) was used to determine the relative frequency of this CNV in DNA from a series of 16 CML patients (both with and without a der(9) deletion) together with DNA derived from 36 paediatric solid tumors in comparison to the incidence of CNV in control DNA. CNV14q12 was present in approximately 50% of both tumor and CML DNA, but was found in 72% of CML bearing a der(9) microdeletion. Chi square analysis found a statistically significant difference (p <or= 0.001) between the incidence of this CNV in cancer and normal DNA and a slightly increased incidence in CML with deletions in comparison to those CML without a detectable deletion. CONCLUSION: The increased incidence of CNV14q12 in tumor samples suggests that either acquired or inherited genomic variation of this new class of variation may be associated with onset or progression of neoplasia.

Child↗
PubMed2005

SNP genotyping to screen for a common deletion in CHARGE syndrome.

BACKGROUND: CHARGE syndrome is a complex of birth defects including coloboma, choanal atresia, ear malformations and deafness, cardiac defects, and growth delay. We have previously hypothesized that CHARGE syndrome could be caused by unidentified genomic microdeletion, but no such deletion was detected using short tandem repeat (STR) markers spaced an average of 5 cM apart. Recently, microdeletion at 8q12 locus was reported in two patients with CHARGE, although point mutation in CHD7 on chromosome 8 was the underlying etiology in most of the affected patients. METHODS: We have extended our previous study by employing a much higher density of SNP markers (3258) with an average spacing of approximately 800 kb. These SNP markers are diallelic and, therefore, have much different properties for detection of deletions than STRs. RESULTS: A global error rate estimate was produced based on Mendelian inconsistency. One marker, rs431722 exceeded the expected frequency of inconsistencies, but no deletion could be demonstrated after retesting the 4 inconsistent pedigrees with local flanking markers or by FISH with the corresponding BAC clone. Expected deletion detection (EDD) was used to assess the coverage of specific intervals over the genome by deriving the probability of detecting a common loss of heterozygosity event over each genomic interval. This analysis estimated the fraction of unobserved deletions, taking into account the allele frequencies at the SNPs, the known marker spacing and sample size. CONCLUSIONS: The results of our genotyping indicate that more than 35% of the genome is included in regions with very low probability of a deletion of at least 2 Mb.

Abnormalities, Multiple↗