TY  - JOUR
A1  - Zahnleiter, Diana
A1  - Uebe, Steffen
A1  - Ekici, Arif B.
A1  - Hoyer, Juliane
A1  - Wiesener, Antje
A1  - Wieczorek, Dagmar
A1  - Kunstmann, Erdmute
A1  - Reis, André
A1  - Doerr, Helmuth-Guenther
A1  - Rauch, Anita
A1  - Thiel, Christian T.
T1  - Rare Copy Number Variants Are a Common Cause of Short Stature
JF  - PLoS Genetics
N2  - Human growth has an estimated heritability of about 80%-90%. Nevertheless, the underlying cause of shortness of stature remains unknown in the majority of individuals. Genome-wide association studies (GWAS) showed that both common single nucleotide polymorphisms and copy number variants (CNVs) contribute to height variation under a polygenic model, although explaining only a small fraction of overall genetic variability in the general population. Under the hypothesis that severe forms of growth retardation might also be caused by major gene effects, we searched for rare CNVs in 200 families, 92 sporadic and 108 familial, with idiopathic short stature compared to 820 control individuals. Although similar in number, patients had overall significantly larger CNVs \((p-value <1 x 10^{-7})\). In a gene-based analysis of all non-polymorphic CNVs >50 kb for gene function, tissue expression, and murine knock-out phenotypes, we identified 10 duplications and 10 deletions ranging in size from 109 kb to 14 Mb, of which 7 were de novo (p < 0.03) and 13 inherited from the likewise affected parent but absent in controls. Patients with these likely disease causing 20 CNVs were smaller than the remaining group (p < 0.01). Eleven (55%) of these CNVs either overlapped with known microaberration syndromes associated with short stature or contained GWAS loci for height. Haploinsufficiency (HI) score and further expression profiling suggested dosage sensitivity of major growth-related genes at these loci. Overall 10% of patients carried a disease-causing CNV indicating that, like in neurodevelopmental disorders, rare CNVs are a frequent cause of severe growth retardation.
KW  - genetic skeletal disorders
KW  - microdeletion syndrome
KW  - mental retardation
KW  - growth failure
KW  - deletion
KW  - classification
KW  - association
KW  - mutations
KW  - genome
KW  - abnormalities
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127645
SN  - 1553-7404
VL  - 9
IS  - 3
ER  -