Evidence That Non-Syndromic Familial Tall Stature Has an Oligogenic Origin Including Ciliary Genes.

Birgit Weiss,Christiaan De Bruin,Hermine A Van Duyvenvoorde,Katrin Hinderhofer,Julian C Lui,Ralph Roeth,Birgit Eberle,Nagarajan Paramasivam,Jan M Wit,Gudrun A Rappold,Jeffrey Baron

doi:10.3389/fendo.2021.660731

Abstract

Human growth is a complex trait. A considerable number of gene defects have been shown to cause short stature, but there are only few examples of genetic causes of non-syndromic tall stature. Besides rare variants with large effects and common risk alleles with small effect size, oligogenic effects may contribute to this phenotype. Exome sequencing was carried out in a tall male (height 3.5 SDS) and his parents. Filtered damaging variants with high CADD scores were validated by Sanger sequencing in the trio and three other affected and one unaffected family members. Network analysis was carried out to assess links between the candidate genes, and the transcriptome of murine growth plate was analyzed by microarray as well as RNA Seq. Heterozygous gene variants in CEP104, CROCC, NEK1, TOM1L2, and TSTD2 predicted as damaging were found to be shared between the four tall family members. Three of the five genes (CEP104, CROCC, and NEK1) belong to the ciliary gene family. All genes are expressed in mouse growth plate. Pathway and network analyses indicated close functional connections. Together, these data expand the spectrum of genes with a role in linear growth and tall stature phenotypes.

Highlights

Human height is a highly polygenic complex trait, largely determined by genetics
Our genetic analysis in this family with non-syndromic extreme tall stature argues for an oligogenic origin
Twenty-eight variants were tested and five variants in Centrosomal Protein 104 (CEP104), CROCC, NEK1, Target Of Myb1-Like 2 (TOM1L2), and Thiosulfate Sulfurtransferaselike Domain containing 2 (TSTD2) were found to be shared in all tall individuals of the index family

Summary

Introduction

Human height is a highly polygenic complex trait, largely determined by genetics. Most of our understanding of the genetic architecture of height has derived from children with abnormal growth patterns and single gene defects (rare variants of large effect) [1, 2]. At the other end of the spectrum, polygenic risk, measured as the sum of thousands of common risk alleles with small effects contributes to height [3]. Oligogenic effects fall between these two extremes, which—so far—have not been well characterized. Evidence has accumulated over the last few years that clinical outcomes can be influenced or modulated by the concerted action of small numbers of rare gene variants, giving rise to oligogenic traits.

Methods

Results

Conclusion