Down syndrome phenotype in a boy with a mosaic microduplication of chromosome 21q22

Schnabel, Franziska; Smogavec, Mateja; Funke, Rudolf; Pauli, Silke; Burfeind, Peter; Bartels, Iris

doi:10.1186/s13039-018-0410-4

Cited by 12 publications

(7 citation statements)

References 25 publications

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“…DYRK1A is of interest for inhibitor development due to its purported roles in the development and progression of neurodegenerative disorders such as Alzheimer’s Disease (AD), Huntington’s Disease (HD), and Parkinson’s Disease (PD). − The DYRK1A gene is located on the Down’s syndrome critical region of chromosome 21, consequently, individuals with Down’s syndrome express elevated levels of DYRK1A protein . Microduplication of the DYRK1A gene resulted in dysmorphic and intellectual features characteristic of a Down’s syndrome phenotype, supporting the hypothesis that DYRK1A represents a novel target for the treatment of Down’s syndrome . Increased tau phosphorylation is observed in trisomy , and Down’s syndrome is associated with early onset AD, underscoring a genetic link between DYRK1A, AD, and Down’s syndrome. − …”

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confidence: 99%

Mining Public Domain Data to Develop Selective DYRK1A Inhibitors

Henderson

Sorrell

Bennett

et al. 2020

ACS Med. Chem. Lett.

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Kinases represent one of the most intensively pursued groups of targets in modern-day drug discovery. Often it is desirable to achieve selective inhibition of the kinase of interest over the remaining ∼500 kinases in the human kinome. This is especially true when inhibitors are intended to be used to study the biology of the target of interest. We present a pipeline of open-source software that analyzes public domain data to repurpose compounds that have been used in previous kinase inhibitor development projects. We define the dual-specificity tyrosine-regulated kinase 1A (DYRK1A) as the kinase of interest, and by addition of a single methyl group to the chosen starting point we remove glycogen synthase kinase β (GSK3β) and cyclin-dependent kinase (CDK) inhibition. Thus, in an efficient manner we repurpose a GSK3β/CDK chemotype to deliver 8b, a highly selective DYRK1A inhibitor.

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mentioning

confidence: 99%

Mining Public Domain Data to Develop Selective DYRK1A Inhibitors

Henderson

Sorrell

Bennett

et al. 2020

ACS Med. Chem. Lett.

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“…Finally, it would be worthwhile to discuss a further report from the literature [ 27 ]: a 5 1/2-year-old boy with a clear clinical diagnosis of DS and an interesting cytogenetic profile. Indeed, FISH and array-CGH analysis showed a mosaic pattern with a microduplication in approximately 40% of lymphocytes and in approximately 80% of buccal mucosa cells, involving 2.56 Mb of the chromosomal region 21q22.13q22.2, in particular arr[GRCh38]21q22.13q22.2(37296053_39815527) × 3 dn.…”

Section: Discussionmentioning

confidence: 99%

Partial trisomy 21 with or without highly restricted Down syndrome critical region (HR-DSCR): report of two new cases and reanalysis of the genotype–phenotype association

Pelleri

Locatelli²,

Mattina

et al. 2022

BMC Med Genomics

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Background Down syndrome (DS) is caused by the presence of an extra copy of full or partial human chromosome 21 (Hsa21). Partial (segmental) trisomy 21 (PT21) is the duplication of only a delimited region of Hsa21 and can be associated or not to DS: the study of PT21 cases is an invaluable model for addressing genotype–phenotype correlation in DS. Previous works reported systematic reanalyses of 132 subjects with PT21 and allowed the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. Methods We report clinical data and cytogenetic analysis of two children with PT21, one with DS and the other without DS. Moreover, we performed a systematic bibliographic search for any new PT21 report. Results Clinical and cytogenetic analyses of the two PT21 children have been reported: in Case 1 the duplication involves the whole long arm of Hsa21, except for the last 2.7 Mb, which are deleted as a consequence of an isodicentric 21: the HR-DSCR is within the duplicated regions and the child is diagnosed with DS. In Case 2 the duplication involves 7.1 Mb of distal 21q22, with a deletion of 2.1 Mb of proximal 20p, as a consequence of an unbalanced translocation: the HR-DSCR is not duplicated and the child presents with psychomotor development delay but no clinical signs of DS. Furthermore, two PT21 reports recently published (named Case 3 and 4) have been discussed: Case 3 has DS diagnosis, nearly full trisomy for Hsa21 and a monosomy for the 21q22.3 region. Case 4 is a baby without DS and a 0.56-Mb duplication of 21q22.3. Genotype–phenotype correlation confirmed the presence of three copies of the HR-DSCR in all DS subjects and two copies in all non-DS individuals. Conclusions The results presented here are fully consistent with the hypothesis that the HR-DSCR is critically associated with DS diagnosis. No exception to this pathogenetic model was found. Further studies are needed to detect genetic determinants likely located in the HR-DSCR and possibly responsible for core DS features, in particular intellectual disability.

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“…Finally, it would be worthwhile to discuss a further report from the literature [27]: a 5 1/2-year-old boy with a clear clinical diagnosis of DS and an interesting cytogenetic pro le. Indeed, FISH and array-CGH analysis showed a mosaic pattern with a microduplication in approximately 40% of lymphocytes and in approximately 80% of buccal mucosa cells, involving 2.56 Mb of the chromosomal region 21q22.13q22.2, in particular arr[GRCh38]21q22.13q22.2(37296053_39815527)x3 dn.…”

Section: Discussionmentioning

confidence: 99%

Partial trisomy 21 with or without highly restricted-Down syndrome critical region (HR- DSCR). Report of two new cases and reanalysis of the genotype-phenotype association

Pelleri

Locatelli

Mattina

et al. 2022

Preprint

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Background Down syndrome (DS) is caused by the presence of an extra copy of full or partial human chromosome 21 (Hsa21). Partial (segmental) trisomy 21 (PT21) is the duplication of only a delimited region of Hsa21 and can be associated or not to DS: the study of PT21 cases is an invaluable model for addressing genotype-phenotype correlation in DS. Previous works reported systematic reanalyses of 132 subjects with PT21 and allowed the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. Methods We report clinical data and cytogenetic analysis of two children with PT21, one with DS and the other without DS. Moreover, we performed a systematic bibliographic search for any new PT21 report. Results Clinical and cytogenetic analyses of the two PT21 children have been reported: in Case 1 the duplication involves the whole long arm of Hsa21, except for the last 2.7 Mb, which are deleted as a consequence of an isodicentric 21: the HR-DSCR is within the duplicated regions and the child is diagnosed with DS. In Case 2 the duplication involves 7.1 Mb of distal 21q22, with a deletion of 2.1 Mb of proximal 20p, as a consequence of an unbalanced translocation: the HR-DSCR is not duplicated and the child presents with psychomotor development delay but no clinical signs of DS. Furthermore, two PT21 reports recently published (named Case 3 and 4) have been discussed: Case 3 has DS diagnosis, nearly full trisomy for Hsa21 and a monosomy for the 21q22.3 region. Case 4 is a baby without DS and a 0.56-Mb duplication of 21q22.3. Genotype-phenotype correlation confirmed the presence of three copies of the HR-DSCR in all DS subjects and two copies in all non-DS individuals. Conclusions The results presented here are fully consistent with the hypothesis that the HR-DSCR is critically associated with DS diagnosis. No exception to this pathogenetic model was found. Further studies are needed to detect genetic determinants likely located in the HR-DSCR and possibly responsible for core DS features, in particular intellectual disability.

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Down syndrome phenotype in a boy with a mosaic microduplication of chromosome 21q22

Cited by 12 publications

References 25 publications

Mining Public Domain Data to Develop Selective DYRK1A Inhibitors

Mining Public Domain Data to Develop Selective DYRK1A Inhibitors

Partial trisomy 21 with or without highly restricted Down syndrome critical region (HR-DSCR): report of two new cases and reanalysis of the genotype–phenotype association

Partial trisomy 21 with or without highly restricted-Down syndrome critical region (HR- DSCR). Report of two new cases and reanalysis of the genotype-phenotype association

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