Duyvenvoorde - Copy number variants in patients with short stature

Hermine A van Duyvenvoorde, Julian C Lui, Sarina G Kant, Wilma
Oostdijk, Antoinet CJ Gijsbers, Mariëtte JV Hoffer, Marcel Karperien,
Marie JE Walenkamp, Cees Noordam, Paul G Voorhoeve, Verónica
Mericq, Alberto M Pereira, Hedi L Claahsen-van de Grinten, Sandy A
van Gool, Martijn H Breuning, Monique Losekoot, Jeffrey Baron,
Claudia AL Ruivenkamp and Jan M Wit

European Journal of Human Genetics - 2014


Height is a highly heritable and classic polygenic trait. Recent
genome-wide association studies (GWAS) have revealed that
at least 180 genetic variants influence adult height. However,
these variants explain only about 10% of the phenotypic
variation in height. Genetic analysis of short individuals can
lead to the discovery of novel rare gene defects with a large
effect on growth. In an effort to identify novel genes associated
with short stature, genome-wide analysis for copy number
variants (CNVs), using single-nucleotide polymorphism arrays,
in 162 patients (149 families) with short stature was
performed. Segregation analysis was performed if possible, and
genes in CNVs were compared with information from GWAS,
gene expression in rodents’ growth plates and published
information. CNVs were detected in 40 families. In six families,
a known cause of short stature was found (SHOX deletion or
duplication, IGF1R deletion), in two combined with a de novo
potentially pathogenic CNV. Thirty-three families had one or
more potentially pathogenic CNVs (n=40). In 24 of these
families, segregation analysis could be performed, identifying
three de novo CNVs and nine CNVs segregating with short
stature. Four were located near loci associated with height in
six CNVs known to be causative for short stature, 40 CNVs with
possible pathogenicity were identified. Segregation studies and
bioinformatics analysis suggested various potential candidate