TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum.


Journal Article

Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders.

Full Text

Cited Authors

  • Davis, EE; Zhang, Q; Liu, Q; Diplas, BH; Davey, LM; Hartley, J; Stoetzel, C; Szymanska, K; Ramaswami, G; Logan, CV; Muzny, DM; Young, AC; Wheeler, DA; Cruz, P; Morgan, M; Lewis, LR; Cherukuri, P; Maskeri, B; Hansen, NF; Mullikin, JC; Blakesley, RW; Bouffard, GG; NISC Comparative Sequencing Program, ; Gyapay, G; Rieger, S; Tönshoff, B; Kern, I; Soliman, NA; Neuhaus, TJ; Swoboda, KJ; Kayserili, H; Gallagher, TE; Lewis, RA; Bergmann, C; Otto, EA; Saunier, S; Scambler, PJ; Beales, PL; Gleeson, JG; Maher, ER; Attié-Bitach, T; Dollfus, H; Johnson, CA; Green, ED; Gibbs, RA; Hildebrandt, F; Pierce, EA; Katsanis, N

Published Date

  • March 2011

Published In

Volume / Issue

  • 43 / 3

Start / End Page

  • 189 - 196

PubMed ID

  • 21258341

Pubmed Central ID

  • 21258341

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/ng.756


  • eng

Conference Location

  • United States