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

Nadine Hauer ,Christian T Thiel,Christian Büttner,Christiane Zweier,Martin Zenker,Dagmar Wieczorek,Bernt Popp,Anita Rauch,Leila Taher,Antje Wiesener,Tilman Rohrer ,Carina Vogl,Cornelia Kraus,Steffen Uebe,Anna Marie Jung ,Fulvia Ferrazzi,Heinrich Sticht,Arif B Ekici,H G Doerr ,Erdmute Kunstmann,Rami Abou Jamra,Perundurai S Dhandapany,Alessandro De Luca,Patrizia Klinger

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.

Highlights

Human height is a heritable and highly heterogeneous trait [1]
Characterization of involved variants and genes and consideration of independent affected individuals carrying these variants revealed 63 candidate genes in 92 (36%) of the 254 affected individuals included in the analysis
Val85Ala variant affects the width of the pocket. g Distribution of the 63 high- and medium-confidence candidate genes in the growthassociated clusters classified 13 genes as high-confidence genes and the remaining 50 genes as medium-confidence candidates (Tables 2 and 4, Supplementary Tables 7 and 11, and Supplementary Figures 6–18)

Summary

Introduction

Human height is a heritable and highly heterogeneous trait [1]. Efforts to understand the genetic basis of growth have employed genome-wide association studies (GWAS) to systematically assess the effect on human height variation of common variants with a minor allele frequency > 5% [2]. 697 variants, mainly located in 423 noncoding loci, have been implicated in height variance in the population [2, 3]. Rare and common height-associated variants together explain about 27.4% of height heritability [3]. In a recent study combining systematic phenotyping and exome-based sequencing, we were able to identify a genetic cause in up to 33% of individuals with idiopathic short stature (ISS) [5]. At least 477 genes have been found to affect human growth [13], but as yet there are no reliable estimates of the number of growthassociated genes For most of these genes, though, no association with short stature has been found in humans. Affected individuals and their families would benefit from the identification of further genes associated with growth retardation. In this study in 254 unrelated individuals with ISS and their families, we used exome sequencing to identify and characterize novel candidate genes based on evolutionarily conserved networks

Methods

Results

Conclusion