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

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.

Fig. 1

Enrichment analysis and candidate gene characterization. a Functional clustering of 1,025 known growth and short stature genes (b) into 29 biological clusters for growth. c Variant level assessment. Number of variants affecting function or likely affecting function and variants of unknown significance identified (Supplementary Tables 1, 2). d Categories of gene level assessment. Numbers represent the genes to which each category applies (see Supplementary Table 4). Numbers in brackets represent the genes among all selected known growth and short-stature genes. e The results of the variant and gene level evaluation were merged to a combined score (Shown is the highest score for each gene, Supplementary Table 5). f Based on structure analysis of variants of unknown significance (VUS), 5 variants in 4 of the high-confidence candidate genes were reclassified to likely pathogenic. Model of the RASA3 C2-domain showing the site of the Asp82Glu and Val85Ala variants. Both residues are located in a pocket of the C2 domains that contains two Ca²⁺ ions (Ca). Asp82 forms interactions with both Ca²⁺ ions (green dotted lines), whereas the longer glutamate side chain of the Asp82Glu variant can only interact with one of the Ca²⁺ ions, probably leading to a loss of the second Ca²⁺ ion from the binding pocket. Val85 (blue) is located on the lateral wall of this pocket, and the shorter alanine side chain in the Val85Ala variant affects the width of the pocket. g Distribution of the 63 high- and medium-confidence candidate genes in the growth-associated clusters