Improved molecular diagnostics of idiopathic short stature and allied disorders: quantitative polymerase chain reaction-based copy number profiling of SHOX and pseudoautosomal region 1.
BACKGROUND
Short stature has an incidence of three in 100 in children. Reliable molecular genetic testing may be crucial in the context of beneficial disease management. Deletions spanning or surrounding the SHOX gene account for a significant proportion of patients with idiopathic short stature (ISS) and allied disorders, such as Leri-Weill dyschondrosteosis.


OBJECTIVE
Several shortcomings of current strategies for copy number profiling of the SHOX region prompted us to develop an improved test for molecular diagnostics of the SHOX region.


RESULTS
We introduced a quantitative PCR (qPCR)-based copy number profiling test, consisting of 11 amplicons targeting clinically relevant regions, i.e. the SHOX gene and regulatory regions. To ensure an optimal sensitivity and specificity, this test was validated in 32 controls and 18 probands with previously identified copy number changes. In addition, 152 probands with SHOX-associated phenotypes were screened, revealing 10 novel copy number changes.


CONCLUSIONS
This highly validated qPCR test supersedes other approaches for copy number screening of the SHOX region in terms of reliability, accuracy, and cost efficiency. In addition, another strong point is the fact that it can be easily implemented in any standard equipped molecular laboratory. Our qPCR-based test is highly recommended for molecular diagnostics of idiopathic short stature and allied disorders.
D'haene
Barbara
B
Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
Hellemans
Jan
J
Craen
Margarita
M
De Schepper
Jean
J
Devriendt
Koen
K
Fryns
Jean-Pierre
JP
Keymolen
Kathelijn
K
Debals
Eveline
E
de Klein
Annelies
A
de Jong
Elisabeth M
EM
Segers
Karin
K
De Paepe
Anne
A
Mortier
Geert
G
Vandesompele
Jo
J
De Baere
Elfride
E
D001827:Body Height / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics; D015331:Cohort Studies; D003198:Computer Simulation; D004247:DNA / Q000235:genetics; D056915:DNA Copy Number Variations; D017931:DNA Primers; D005784:Gene Amplification; D006130:Growth Disorders / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000502:physiology; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074122:Short Stature Homeobox Protein
D017931:DNA Primers; D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D004247:DNA