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Molecular and Clinical Characterization of Syndromes Associated With Intellectual Disability
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Intellectual disability (ID) affects approximately 1-3% of the population and is defined as having an IQ below 70 as well as a significant limitation in adaptive behavior.

The implementation of chromosomal microarrays (CMA) into the field of clinical genetics has revolutionized the ability to find genetic aberrations responsible for different genetic disorders. Importantly. these technologies have allowed several new microdeletion and microduplication aberrations to be identified that otherwise would have escaped detection using more conventional methods. Finding the genetic etiology of a syndrome and its association to the phenotype is paramount to better health care, provision of tailored therapy, presymptomatic screening, accurate prognosis, recurrence risk evaluation and in some cases prenatal testing.

Despite the plethora of new information available, there are still a number of clinical and genetic features we do not fully understand.

The aim of this work was to identify regions and syndromes associated with ID by CMA analysis and to make a detailed clinical description of the affected patients’ phenotype.

In paper I we studied the 22q11.2 duplication syndrome and presented two familial cases with a description of both their genotype and phenotype. Additionally, 36 cases harboring the duplication were reviewed to further delineate the phenotype of the syndrome.

In paper II, we revealed two unrelated patients with a deletion at 6q14.1-q15 and a distinct phenotype. Together with one previously reported patient our study suggests that a novel, clinically recognizable microdeletion syndrome exists in these patients.

In paper III the phenotype and genotype of six unrelated patients with partially overlapping microdeletions at 10p12.31-p11.21 were described. Taken together with a previously reported patient we propose that these findings represent a new contiguous gene syndrome.

In paper IV, two sisters; one presenting with two tandem interstitial duplications and the other a large deletion over the same region (6q13-q16) were reported. The reason for the CNVs was a maternal de novo translocation. This is the first case describing the genotype and phenotype of this duplicated region at 6q13-q16.

In conclusion, four different genetic aberrations involved in the etiology of ID and their corresponding phenotypes and candidate genes have been characterized.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 880
Keyword [en]
intellectual disability, 22q11.2 duplication syndrome, 6q deletion, 6q duplication, 10p deletion, developmental delay, mental retardation, dysmorphic features
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-197011ISBN: 978-91-554-8628-0 (print)OAI: oai:DiVA.org:uu-197011DiVA: diva2:612752
Public defence
2013-05-08, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2013-04-17 Created: 2013-03-16 Last updated: 2013-08-30Bibliographically approved
List of papers
1. Clinical variability of the 22q11.2 duplication syndrome
Open this publication in new window or tab >>Clinical variability of the 22q11.2 duplication syndrome
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2008 (English)In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 51, no 6, 501-510 p.Article in journal (Refereed) Published
Abstract [en]

The 22q11.2 duplication syndrome is an extremely variable disorder with a phenotype ranging from normal to learning disability and congenital defects. Both patients with a de novo 22q11.2 duplication and patients in whom the duplication has been inherited from a phenotypically normal parent have been reported. In this study we present two familial cases with a 3Mb 22q11.2 duplication detected by array-CGH. We also review the findings in 36 reported cases with the aim of delineating the phenotype of the 22q11.2 duplication syndrome. In a majority of the reported cases where parents have been tested, the duplication seems to have been inherited from a normal parent with minor abnormalities. With this in mind we recommend that family members of patients with a 22q11.2 duplication to be tested for this genetic defect.

Keyword
22q11.2 Duplication, Syndrome, Mental retardation, Children, Array-CGH, MLPA
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-102229 (URN)10.1016/j.ejmg.2008.07.005 (DOI)000261941700001 ()18707033 (PubMedID)
Note

De två (2) sista författarna delar sistaförfattarskapet.

Available from: 2009-05-07 Created: 2009-05-06 Last updated: 2013-09-17Bibliographically approved
2. Interstitial Deletions at 6q14.1-q15 Associated with Obesity, Developmental Delay and a Distinct Clinical Phenotype
Open this publication in new window or tab >>Interstitial Deletions at 6q14.1-q15 Associated with Obesity, Developmental Delay and a Distinct Clinical Phenotype
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2010 (English)In: Molecular Syndromology, ISSN 1661-8769, E-ISSN 1661-8777, Vol. 1, no 2, 75-81 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND

Interstitial deletions of the long arm of chromosome 6 have been described in several patients with obesity and a Prader-Willi-like phenotype. Haploinsufficiency of the SIM1 gene located at 6q16.3 is suggested as being responsible for the regulation of body weight. Here we report on 2 patients with interstitial deletions at 6q14.1-q15 presenting with obesity and symptoms strikingly similar to those reported for deletions involving the SIM1 gene despite not having a deletion of this gene.

METHODS

Array comparative genomic hybridisation was used to diagnose 2 children with obesity and developmental delay, revealing 2 interstitial deletions at 6q14.1-q15 of 8.73 and 4.50 Mb, respectively, and a region of overlap of 4.2-Mb.

RESULTS

The similar phenotype in the 2 patients was most likely due to a 4.2-Mb common microdeletion at 6q14.1-q15. Another patient has previously been described with an overlapping deletion. The 3 patients share several features, such as developmental delay, obesity, hernia, rounded face with full cheeks, epicanthal folds, short palpebral fissures, bulbous nose, large ears, and syndactyly between toes II and III.

CONCLUSIONS

Together with a previously reported patient, our study suggests that the detected deletions may represent a novel clinically recognisable microdeletion syndrome caused by haploinsufficiency of dosage-sensitive genes in the 6q14.1-q15 region.

Keyword
6q Deletion, Learning disability, Mental retardation, Obesity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-140215 (URN)10.1159/000314025 (DOI)21045960 (PubMedID)
Available from: 2011-01-04 Created: 2011-01-04 Last updated: 2017-12-11Bibliographically approved
3. Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11
Open this publication in new window or tab >>Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11
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2011 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 9, 959-964 p.Article in journal (Refereed) Published
Abstract [en]

With the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has improved considerably. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb. The smallest region of overlap is 306 kb, which includes WAC gene, known to be associated with microtubule function and to have a role in cell division. Another patient has previously been described with a 10Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied. All patients also displayed various visual impairments and six out of seven patients had cardiac malformations. Taken together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage-sensitive genes that predispose to developmental delay.

Keyword
10p deletion, developmental delay, dysmorphic features, learning disability, mental retardation, WAC
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-158299 (URN)10.1038/ejhg.2011.71 (DOI)000294003100009 ()
Available from: 2011-09-07 Created: 2011-09-06 Last updated: 2017-12-08Bibliographically approved
4. Unbalanced de novo translocation in mother resulting in one child with a 6q13-q16 deletion and one child with a 6q13-q16 duplication
Open this publication in new window or tab >>Unbalanced de novo translocation in mother resulting in one child with a 6q13-q16 deletion and one child with a 6q13-q16 duplication
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Here we report on two sisters with reciprocal CNVs at 6q13-q16.1. Both the deletion and the duplication were inherited from the healthy mother carrying an insertion of 6q13-q16 to 15q11. The deleted region in one of the sisters has previously been described. However, to our knowledge this is the first report of a duplication at the region 6q13q16. In the report we submit a detailed phenotypical description of both patients as well as candidate genes for some of the various symptoms that the patients presented.

National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-197354 (URN)
Available from: 2013-03-24 Created: 2013-03-24 Last updated: 2013-09-17Bibliographically approved

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