Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature

Hauer N, Popp B, Taher L, Vogl C, Dhandapany PS, Büttner C, Uebe S, Sticht H, Ferrazzi F, Ekici AB, De Luca A, Klinger P, Kraus C, Zweier C, Wiesener A, Jamra RA, Kunstmann E, Rauch A, Wieczorek D, Jung AM, Rohrer TR, Zenker M, Dörr HG, Reis A, Thiel C (2019)

Publication Type: Journal article

Publication year: 2019

Journal

European Journal of Human Genetics Nature Publishing Group: Open Access Hybrid Model Option B

DOI: 10.1038/s41431-019-0362-0

Abstract

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.

Authors with CRIS profile

Nadine Hauer Lehrstuhl für Humangenetik Bernt Popp Institute of Human Genetics Leila Taher Juniorprofessur für Bioinformatik Christian Büttner Lehrstuhl für Humangenetik Steffen Uebe Institute of Human Genetics Heinrich Sticht Professur für Bioinformatik Fulvia Ferrazzi Institute of Human Genetics Arif Bülent Ekici Institute of Human Genetics Patricia Klinger Lehrstuhl für Funktionelle und Klinische Anatomie Christiane Zweier Medizinische Fakultät Helmuth-Günther Dörr Medizinische Fakultät André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Christian Thiel Medizinische Fakultät

Involved external institutions

Institute for Stem Cell Science and Regenerative Medicine IN India (IN) Casa Sollievo della Sofferenza IT Italy (IT) University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) Universität Leipzig DE Germany (DE) Julius-Maximilians-Universität Würzburg DE Germany (DE) Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) Universität Duisburg-Essen (UDE) DE Germany (DE) Otto-von-Guericke-Universität Magdeburg DE Germany (DE)

How to cite

APA:

Hauer, N., Popp, B., Taher, L., Vogl, C., Dhandapany, P.S., Büttner, C.,... Thiel, C. (2019). Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature. European Journal of Human Genetics. https://doi.org/10.1038/s41431-019-0362-0

MLA:

Hauer, Nadine, et al. "Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature." European Journal of Human Genetics (2019).

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