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

European Journal of Human Genetics : EJHG
Nadine N HauerChristian T Thiel

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 confirmatio...Continue Reading

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Citations

Apr 3, 2020·American Journal of Physiology. Cell Physiology·Wei QuZhibing Zhang
Aug 23, 2020·International Journal of Molecular Sciences·Michal CohenDov Tiosano
Jul 2, 2021·Frontiers in Endocrinology·Birgit WeissGudrun A Rappold

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Methods Mentioned

BETA
ISS
exome sequencing
ubiquitination

Software Mentioned

RasMol
DAVID
HHpred
Swiss
SureSelect
Ensembl
MedGen
Modeller
treemap package
Modbase

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