- Library Home /
- Search Collections /
- Open Collections /
- Browse Collections /
- UBC Theses and Dissertations /
- Clinical and molecular analysis of Williams-Beuren...
Open Collections
UBC Theses and Dissertations
UBC Theses and Dissertations
Clinical and molecular analysis of Williams-Beuren syndrome : a search for factors determining clinical variability in a contiguous deletion syndrome Wang, Michael Steve
Abstract
Williams-Beuren syndrome (WBS) is clinically characterized by a distinctive "elfin" facial appearance, short stature, mental retardation, a unique cognitive profile, friendly outgoing personality, and various congenital heart malformations with supravalvular aortic stenosis (SVAS) being the most common. Clinical features seen with less frequency include infantile hypercalcaemia, hoarse voice, hyperacousis, renal hypoplasia, clinodactyly of the 5th finger, and teeth hypoplasia. The syndrome arises as a consequence of a 2 cM deletion of 7qll.23 in 90 - 95% of all clinically typical cases reported to date. This region includes a number of genes that include elastin (ELN) and LEVI kinase 1 (LTMK1). ELN mutations have been found in isolated cases of SVAS while LIMK1 has been implicated in the unique WBS cognitive profile. However, not all patients present with congenital cardiovascular malformations and the severity to which cognition is impaired in WBS individuals varies with each patient. This variability of clinical phenotype presentation in clinically typical cases has not been explained. In order to identify the underlying cause of this variability, clinical and molecular data were analyzed from 108 clinically diagnosed WBS cases. A deletion of 7qll.23 was identified in 85 cases and extended from D7S489U to D7S1870 (including these markers) in the majority of cases. Only two cases were found to have a more distal deletion that also encompassed D7S489L. In these 85 cases, no influence on phenotypic variability was found for deletion extent, parental origin of deletion, ELN and LLMK1 polymorphisms, or gender using a Bonferroni corrected level of significance (α'=4.6x10⁻⁴). Nonetheless, a number of interesting 'suggestive' associations with p<0.05 were identified. Correlations between clinical features of WBS were examined to identify those features which may have a common etiology. Identifying correlates may also identify specific phenotypic features that can be used as a prognostic tool. This has revealed significant correlations between: 1) low birth weight (<10th centile) and low weight at the time of physical examination (<10th centile at the time of examination; p=9.0xl0⁻⁵), and 2) hypercalcemia and presentation of a stellate iris pattern (p=1.0xl0⁻⁵). While not fulfilling the strict criterion (α '=3.3xl0⁻⁴) necessary to reach an experiment-wide false positive rate of less than 5%, a number of interesting suggestive correlations were observed including: 1) stellate and blue irides (p=1.2xl0⁻³), 2) stellate irides and a typical WBS personality (p=6.8xl0⁻³), and 3) renal/urogenital abnormalities and cardiovascular malformations (p=7.9xl0⁻³). These identified associations provide an important starting point for the understanding of the underlying etiology of WBS and will be of interest to confirm in an independent data set.
Item Metadata
Title |
Clinical and molecular analysis of Williams-Beuren syndrome : a search for factors determining clinical variability in a contiguous deletion syndrome
|
Creator | |
Publisher |
University of British Columbia
|
Date Issued |
1999
|
Description |
Williams-Beuren syndrome (WBS) is clinically characterized by a distinctive "elfin"
facial appearance, short stature, mental retardation, a unique cognitive profile, friendly
outgoing personality, and various congenital heart malformations with supravalvular aortic
stenosis (SVAS) being the most common. Clinical features seen with less frequency include
infantile hypercalcaemia, hoarse voice, hyperacousis, renal hypoplasia, clinodactyly of the 5th
finger, and teeth hypoplasia. The syndrome arises as a consequence of a 2 cM deletion of
7qll.23 in 90 - 95% of all clinically typical cases reported to date. This region includes a
number of genes that include elastin (ELN) and LEVI kinase 1 (LTMK1). ELN mutations have
been found in isolated cases of SVAS while LIMK1 has been implicated in the unique WBS
cognitive profile. However, not all patients present with congenital cardiovascular
malformations and the severity to which cognition is impaired in WBS individuals varies with
each patient. This variability of clinical phenotype presentation in clinically typical cases has
not been explained.
In order to identify the underlying cause of this variability, clinical and molecular data
were analyzed from 108 clinically diagnosed WBS cases. A deletion of 7qll.23 was
identified in 85 cases and extended from D7S489U to D7S1870 (including these markers) in
the majority of cases. Only two cases were found to have a more distal deletion that also
encompassed D7S489L. In these 85 cases, no influence on phenotypic variability was found
for deletion extent, parental origin of deletion, ELN and LLMK1 polymorphisms, or gender
using a Bonferroni corrected level of significance (α'=4.6x10⁻⁴). Nonetheless, a number of
interesting 'suggestive' associations with p<0.05 were identified.
Correlations between clinical features of WBS were examined to identify those
features which may have a common etiology. Identifying correlates may also identify specific
phenotypic features that can be used as a prognostic tool. This has revealed significant
correlations between: 1) low birth weight (<10th centile) and low weight at the time of
physical examination (<10th centile at the time of examination; p=9.0xl0⁻⁵), and 2)
hypercalcemia and presentation of a stellate iris pattern (p=1.0xl0⁻⁵). While not fulfilling the
strict criterion (α '=3.3xl0⁻⁴) necessary to reach an experiment-wide false positive rate of less
than 5%, a number of interesting suggestive correlations were observed including: 1) stellate
and blue irides (p=1.2xl0⁻³), 2) stellate irides and a typical WBS personality (p=6.8xl0⁻³), and
3) renal/urogenital abnormalities and cardiovascular malformations (p=7.9xl0⁻³). These
identified associations provide an important starting point for the understanding of the
underlying etiology of WBS and will be of interest to confirm in an independent data set.
|
Extent |
6565404 bytes
|
Genre | |
Type | |
File Format |
application/pdf
|
Language |
eng
|
Date Available |
2009-06-16
|
Provider |
Vancouver : University of British Columbia Library
|
Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
|
DOI |
10.14288/1.0089058
|
URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
|
Graduation Date |
1999-11
|
Campus | |
Scholarly Level |
Graduate
|
Aggregated Source Repository |
DSpace
|
Item Media
Item Citations and Data
Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.