AUTHOR=Weiss Birgit , Eberle Birgit , Roeth Ralph , de Bruin Christiaan , Lui Julian C. , Paramasivam Nagarajan , Hinderhofer Katrin , van Duyvenvoorde Hermine A. , Baron Jeffrey , Wit Jan M. , Rappold Gudrun A. TITLE=Evidence That Non-Syndromic Familial Tall Stature Has an Oligogenic Origin Including Ciliary Genes JOURNAL=Frontiers in Endocrinology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.660731 DOI=10.3389/fendo.2021.660731 ISSN=1664-2392 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.