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Published on: February 21, 2015
Two familial microduplications of 15q26.3 causing overgrowth and variable intellectual disability with normal copy
Melanie Leffler1, Sanna Puusepp2, Olga Žilina3
1Genetics of Learning Disability Service, Hunter Genetics, Waratah, Australia.
Abstract:
Terminal duplications of 15q26.3 are associated with an overgrowth phenotype, distinct facial features and intellectual disability, with the smallest reported microduplication to date being 3.16 Mb in size. We report two familial 15q26.3 microduplication cases that are less than half this size, re-defining the minimal critical region for this duplication syndrome. In both families the duplication (albeit a complex copy number gain in one family) is associated with tall stature, early speech delay and variable cognitive problems. Neither familial copy number gains encompass the gene encoding for the insulin-like growth factor 1 receptor (IGF1R), the most-cited candidate for the overgrowth phenotype. In one family, whole genome sequence data and break point mapping excludes disruption of known IGF1R regulatory elements due to potential insertion within these elements. These cases highlight the possibility that the distal region of 15q contains another gene regulating human growth, with LRRK1 being a potential candidate.
Insights
Two familial 15q26.3 microduplications, smaller than previously known, redefine the critical region for this overgrowth syndrome. These cases suggest other genes, not IGF1R, may regulate human growth.
Area of Science:
- Human Genetics
- Genomic Medicine
- Developmental Biology
Background:
- Terminal duplications of 15q26.3 are linked to overgrowth, distinct facial features, and intellectual disability.
- The smallest previously reported microduplication was 3.16 Mb.
Purpose of the Study:
- To report two familial 15q26.3 microduplication cases smaller than previously identified.
- To redefine the minimal critical region for 15q26.3 duplication syndrome.
- To investigate potential novel growth-regulating genes in the 15q26.3 region.
Main Methods:
- Case reporting of two familial microduplications.
- Breakpoint mapping and whole-genome sequencing.
- Analysis of gene content within the duplicated regions.
Main Results:
- Two familial 15q26.3 microduplications, less than half the previously smallest size, were identified.
- Associated phenotypes include tall stature, early speech delay, and variable cognitive issues.
- The insulin-like growth factor 1 receptor (IGF1R) gene was not encompassed in either duplication, and its regulatory elements were not disrupted.
Conclusions:
- The minimal critical region for 15q26.3 duplication syndrome is smaller than previously defined.
- The overgrowth phenotype may be regulated by genes other than IGF1R in this region.
- LRRK1 is a potential candidate gene for regulating human growth in the 15q26.3 region.
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