TY - JOUR
T1 - Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature
AU - Hauer, Nadine N
AU - Popp, Bernt
AU - Taher, Leila
AU - Vogl, Carina
AU - Dhandapany, Perundurai S
AU - Büttner, Christian
AU - Uebe, Steffen
AU - Sticht, Heinrich
AU - Ferrazzi, Fulvia
AU - Ekici, Arif B
AU - De Luca, Alessandro
AU - Klinger, Patrizia
AU - Kraus, Cornelia
AU - Zweier, Christiane
AU - Wiesener, Antje
AU - Jamra, Rami Abou
AU - Kunstmann, Erdmute
AU - Rauch, Anita
AU - Wieczorek, Dagmar
AU - Jung, Anna-Marie
AU - Rohrer, Tilman R
AU - Zenker, Martin
AU - Doerr, Helmuth-Guenther
AU - Reis, André
AU - Thiel, Christian T
PY - 2019/7
Y1 - 2019/7
N2 - Height is a heritable and highly heterogeneous trait. Short stature affects 3% of the population and in most cases is genetic in origin. After excluding known causes, 67% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36%) independent families. Based on systematic characterization of variants and functional analysis including expression in chondrocytes, we classified 13 genes as strong candidates. Whereas variants in at least two families were detected for all 13 candidates, two genes had variants in 6 (UBR4) and 8 (LAMA5) families, respectively. To facilitate their characterization, we established a clustered network of 1025 known growth and short stature genes, which yielded 29 significantly enriched clusters, including skeletal system development, appendage development, metabolic processes, and ciliopathy. Eleven of the candidate genes mapped to 21 of these clusters, including CPZ, EDEM3, FBRS, IFT81, KCND1, PLXNA3, RASA3, SLC7A8, UBR4, USP45, and ZFHX3. Fifty additional growth-related candidates we identified await confirmation in other affected families. Our study identifies Mendelian forms of growth retardation as an important component of idiopathic short stature.
AB - Height is a heritable and highly heterogeneous trait. Short stature affects 3% of the population and in most cases is genetic in origin. After excluding known causes, 67% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36%) independent families. Based on systematic characterization of variants and functional analysis including expression in chondrocytes, we classified 13 genes as strong candidates. Whereas variants in at least two families were detected for all 13 candidates, two genes had variants in 6 (UBR4) and 8 (LAMA5) families, respectively. To facilitate their characterization, we established a clustered network of 1025 known growth and short stature genes, which yielded 29 significantly enriched clusters, including skeletal system development, appendage development, metabolic processes, and ciliopathy. Eleven of the candidate genes mapped to 21 of these clusters, including CPZ, EDEM3, FBRS, IFT81, KCND1, PLXNA3, RASA3, SLC7A8, UBR4, USP45, and ZFHX3. Fifty additional growth-related candidates we identified await confirmation in other affected families. Our study identifies Mendelian forms of growth retardation as an important component of idiopathic short stature.
U2 - 10.1038/s41431-019-0362-0
DO - 10.1038/s41431-019-0362-0
M3 - Article
C2 - 30809043
SN - 1018-4813
VL - 27
SP - 1061
EP - 1071
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 7
ER -