An Interstitial 20q11.21 Microdeletion Causing Mild Intellectual Disability and Facial Dysmorphisms

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Abstract

We report a case of an interstitial chromosome 20q11.21 microdeletion in a 7-year-old male child presenting with mild intellectual disability and facial dysmorphisms. Array comparative genomic hybridization (CGH) has shown that the deletion resulted in the loss of 68 genes, among which 5 genes ( COX4I2, MYLK2, ASXL1, DNMT3B, and SNTA1) are disease causing. The size of the deletion was estimated to span 2.6 Mb. Only three cases of deletions encompassing this chromosomal region have been reported. The phenotype of the index patient was found to resemble the mildest cases of Bohring-Opitz syndrome that is caused by ASXL1 mutations. An in silico evaluation of the deleted genomic region has shown that benign genomic variations have never been observed to affect the ASXL1 gene, in contrast to the other disease-causing genes. As a result, it was suggested that ASXL1 loss is likely to be the main cause of the phenotypic manifestations. The present case report indicates that a loss of the disease-causing gene can produce a milder phenotype of a single gene condition.

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De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome.

Colin R McGowan, Andrea De Martino, Maarit Peippo … (2011)

Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.

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Somatic Genome Variations in Health and Disease

I.Y. Iourov, S.G Vorsanova, Y.B. Yurov (2010)

It is hard to imagine that all the cells of the human organism (about 1014) share identical genome. Moreover, the number of mitoses (about 1016) required for the organism’s development and maturation during ontogeny suggests that at least a proportion of them could be abnormal leading, thereby, to large-scale genomic alterations in somatic cells. Experimental data do demonstrate such genomic variations to exist and to be involved in human development and interindividual genetic variability in health and disease. However, since current genomic technologies are mainly based on methods, which analyze genomes from a large pool of cells, intercellular or somatic genome variations are significantly less appreciated in modern bioscience. Here, a review of somatic genome variations occurring at all levels of genome organization (i.e. DNA sequence, subchromosomal and chromosomal) in health and disease is presented. Looking through the available literature, it was possible to show that the somatic cell genome is extremely variable. Additionally, being mainly associated with chromosome or genome instability (most commonly manifesting as aneuploidy), somatic genome variations are involved in pathogenesis of numerous human diseases. The latter mainly concerns diseases of the brain (i.e. autism, schizophrenia, Alzheimer’s disease) and immune system (autoimmune diseases), chromosomal and some monogenic syndromes, cancers, infertility and prenatal mortality. Taking into account data on somatic genome variations and chromosome instability, it becomes possible to show that related processes can underlie non-malignant pathology such as (neuro)degeneration or other local tissue dysfunctions. Together, we suggest that detection and characterization of somatic genome behavior and variations can provide new opportunities for human genome research and genetics.

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Molecular Cytogenetics and Cytogenomics of Brain Diseases

I.Y. Iourov, S.G Vorsanova, Y.B. Yurov (2008)

Molecular cytogenetics is a promising field of biomedical research that has recently revolutionized our thinking on genome structure and behavior. This is in part due to discoveries of human genomic variations and their contribution to biodiversity and disease. Since these studies were primarily targeted at variation of the genome structure, it appears apposite to cover them by molecular cytogenomics. Human brain diseases, which encompass pathogenic conditions from severe neurodegenerative diseases and major psychiatric disorders to brain tumors, are a heavy burden for the patients and their relatives. It has been suggested that most of them, if not all, are of genetic nature and several recent studies have supported the hypothesis assuming them to be associated with genomic instabilities (i.e. single-gene mutations, gross and subtle chromosome imbalances, aneuploidy). The present review is focused on the intriguing relationship between genomic instability and human brain diseases. Looking through the data, we were able to conclude that both interindividual and intercellular genomic variations could be pathogenic representing, therefore, a possible mechanism for human brain malfunctioning. Nevertheless, there are still numerous gaps in our knowledge concerning the link between genomic variations and brain diseases, which, hopefully, will be filled by forthcoming studies. In this light, the present review considers perspectives of this dynamically developing field of neurogenetics and genomics.

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Author and article information

Journal

Journal ID (nlm-ta): Case Rep Genet

Journal ID (iso-abbrev): Case Rep Genet

Journal ID (publisher-id): CRIM.GENETICS

Title: Case Reports in Genetics

Publisher: Hindawi Publishing Corporation

ISSN (Print): 2090-6544

ISSN (Electronic): 2090-6552

Publication date (Print): 2013

Publication date (Electronic): 14 February 2013

Volume: 2013

Electronic Location Identifier: 353028

Affiliations

¹Mental Health Research Center, Russian Academy of Medical Sciences, Moscow 119152, Russia

²Institute of Pediatrics and Children Surgery, Ministry of Health of the Russian Federation, Moscow 125412, Russia

³Moscow City University of Psychology and Education, Moscow 127051, Russia

Author notes

*Ivan Y. Iourov: ivan.iourov@ 123456gmail.com

Academic Editors: S. Ennis, S. Paracchini, J. L. Royo, and M. Velinov

Article

DOI: 10.1155/2013/353028

PMC ID: 3586477

PubMed ID: 23476833

SO-VID: 43424ac3-f998-49e4-8891-e93656529e75

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.