Characterization of a de novo complex chromosome rearrangement (CCR) involving chromosomes 2 and 12, associated with mental retardation and impaired speech development

Ullmann, Reinhard; Schubert, Marei; Ledinegg, M.; Ofner, Lisa; Windpassinger, Christian; Wagner, Kay Uwe; Kroisel, Peter M.; Petek, Erwin

doi:10.1159/000094804

Cited by 6 publications

(7 citation statements)

References 43 publications

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“…Highly complex chromosome aberrations with multiple breakpoints have recently been reported in numerous patients (e.g. [Houge et al, 2003; Schwarzbraun et al, 2006; Sensi et al, 2008; Ballarati et al, 2009; Poot et al, 2010]), but the underlying mechanisms of such rearrangements remained largely elusive. Also in the present case we have failed to identify any conspicuous features of chromosome architecture, for example, the presence of homologous segmental duplications at the breakpoints on chromosomes 2, 4, and 5 that could give some hint on the underlying mechanism of this complex interchromosomal rearrangement.…”

Section: Discussionmentioning

confidence: 99%

Characterization of an interstitial 4q32 deletion in a patient with mental retardation and a complex chromosome rearrangement

Tzschach

Menzel

Erdogan

et al. 2010

American J of Med Genetics Pt A

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Interstitial deletions of chromosome band 4q32 are rare. We report on a 22-year-old female patient with a de novo interstitial deletion of chromosome 4q32 and a balanced translocation t(2;5)(p21;q12.1). Clinical problems of the patient comprised mild to moderate mental retardation, psychosis, obesity, broad nasal root, sparse lateral eyebrows, thin upper lip, short philtrum, micrognathia, and strabismus. Analysis by whole genome array CGH using an Agilent 244K oligonucleotide array and subsequent FISH using BAC clones from the 4q32 region revealed an unexpectedly complex rearrangement comprising a deletion of approximately 10 Mb in 4q32.1q32.3 and the insertion of two small fragments of 0.8 and 0.11 Mb originating from the derivative chromosome 4q32 into derivative chromosome 5q. The breakpoints of the t(2;5) translocation were mapped by BAC-FISH; no genes were disrupted by these breakpoints. The deleted interval in 4q32 harbored more than 30 genes, and haploinsufficiency of one or several of these genes is likely to have caused the clinical problems of the patient. Candidate genes for cognitive defects are GRIA2, GLRB, NPY1R, and NPY5R. In conclusion, this patient increases our knowledge about the phenotypic consequences of interstitial 4q32 deletions. Reports of patients with overlapping deletions will be needed to elucidate the role of individual genes and to establish genotype-phenotype correlations.

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Section: Discussionmentioning

confidence: 99%

Characterization of an interstitial 4q32 deletion in a patient with mental retardation and a complex chromosome rearrangement

Tzschach

Menzel

Erdogan

et al. 2010

American J of Med Genetics Pt A

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“…Given the tiling nature of our BAC clones across the genome, the theoretical resolution of our array is about 75 kb. Although we have shown that this resolution can also be reached in reality [Motazacker et al, 2007;Schwarzbraun et al, 2006], the conservative CNV calling procedure applied in this study resulted in an average functional resolution of about 142 kb as inferred from the mean size of the smallest 10% of CNVs identified in this study. An independent test confirming the reliability of this platform and CNV calling procedure has been published recently [LaFramboise et al, 2009].…”

Section: Array-cghmentioning

confidence: 73%

High frequency of rare copy number variants affecting functionally related genes in patients with structural brain malformations

et al. 2011

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During the past years, significant advances have been made in our understanding of the development of the human brain, and much of this knowledge comes from genetic studies of disorders associated with abnormal brain development. We employed array-comparative genomic hybridization (CGH) to investigate copy number variants (CNVs) in a cohort of 169 patients with various structural brain malformations including lissencephaly, polymicrogyria, focal cortical dysplasia, and corpus callosum agenesis. The majority of the patients had intellectual disabilities (ID) and suffered from symptomatic epilepsy. We detected at least one rare CNV in 38 patients (22.5%). All genes located within the rare CNVs were subjected to enrichment analysis for specific Gene Ontology Terms or Kyoto Encyclopedia of Genes and Genomes pathways and to protein-protein network analysis. Based on these analyses, we propose that genes involved in "axonal transport," "cation transmembrane transporter activity," and the "c-Jun N-terminal kinase (JNK) cascade" play a significant role in the etiology of brain malformations. This is to the best of our knowledge the first systematic study of CNVs in patients with structural brain malformations and our data show that CNVs play an important role in the etiology of these malformations, either as direct causes or as genetic risk factors.

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“…Real‐time PCR was performed as previously described [Schwarzbraun et al, 2006b] and showed that the GCK gene was deleted by a de‐novo mutation, as both her healthy parents did not show a deletion in this genomic segment. Using STR‐marker analysis with markers located within the deletion region we could confirm that the deletion occurred on the paternal allele.…”

Section: Methods and Resultsmentioning

confidence: 99%

MODY type 2 in Greig cephalopolysyndactyly syndrome (GCPS) as part of a contiguous gene deletion syndrome

Zung

Petek

Ben‐Zeev

et al. 2011

American J of Med Genetics Pt A

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Maturity-onset diabetes of the young type 2 (MODY2) is a form of monogenic diabetes, characterized by mild fasting hyperglycemia. MODY2 is caused by heterozygous mutations in the GCK gene that encodes the glucokinase enzyme. We describe the clinical features and the underlying genetic defect of MODY2 in a patient with atypical Greig cephalopolysyndactyly syndrome (GCPS). The patient presented with the limb formation and the craniofacial developmental abnormalities typical to GCPS, in addition to mental retardation and epilepsy (assigned as atypical syndrome). Fasting hyperglycemia in the diabetic range, impaired glucose tolerance, and lack of diabetes autoantibodies were compatible with MODY2. In order to delineate the genetic aberrations relevant both to MODY2 and Greig syndrome in this patient, we performed cytogenetic analysis, real-time PCR of the GCK gene, and comparative genomic hybridization (CGH) array. Cytogenetic study has shown a microscopic detectable deletion in the 7p13-15 chromosomal region. Real-time PCR demonstrated a deletion of the GCK gene in the patient but not her parents, and CGH array revealed a deleted region of approximately 12 Mb in the 7p13-15 region. This deleted region included GLI3 and GCK genes (where heterozygous mutations cause GCPS and MODY2, respectively), and many other contiguous genes. Our patient manifests a unique form of MODY2, where GCK gene deletion is part of a large deleted segment in the 7p13-15 chromosomal region.

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Characterization of a de novo complex chromosome rearrangement (CCR) involving chromosomes 2 and 12, associated with mental retardation and impaired speech development

Cited by 6 publications

References 43 publications

Characterization of an interstitial 4q32 deletion in a patient with mental retardation and a complex chromosome rearrangement

Characterization of an interstitial 4q32 deletion in a patient with mental retardation and a complex chromosome rearrangement

High frequency of rare copy number variants affecting functionally related genes in patients with structural brain malformations

MODY type 2 in Greig cephalopolysyndactyly syndrome (GCPS) as part of a contiguous gene deletion syndrome

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