TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum.
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.
Center for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA.
Erica E
EE
Davis
Qi
Q
Zhang
Qin
Q
Liu
Bill H
BH
Diplas
Lisa M
LM
Davey
Jane
J
Hartley
Corinne
C
Stoetzel
Katarzyna
K
Szymanska
Gokul
G
Ramaswami
Clare V
CV
Logan
Donna M
DM
Muzny
Alice C
AC
Young
David A
DA
Wheeler
Pedro
P
Cruz
Margaret
M
Morgan
Lora R
LR
Lewis
Praveen
P
Cherukuri
Baishali
B
Maskeri
Nancy F
NF
Hansen
James C
JC
Mullikin
Robert W
RW
Blakesley
Gerard G
GG
Bouffard
Gabor
G
Gyapay
Susanne
S
Rieger
Burkhard
B
Tönshoff
Ilse
I
Kern
Neveen A
NA
Soliman
Thomas J
TJ
Neuhaus
Kathryn J
KJ
Swoboda
Hulya
H
Kayserili
Tomas E
TE
Gallagher
Richard A
RA
Lewis
Carsten
C
Bergmann
Edgar A
EA
Otto
Sophie
S
Saunier
Peter J
PJ
Scambler
Philip L
PL
Beales
Joseph G
JG
Gleeson
Eamonn R
ER
Maher
Tania
T
Attié-Bitach
Hélène
H
Dollfus
Colin A
CA
Johnson
Eric D
ED
Green
Richard A
RA
Gibbs
Friedhelm
F
Hildebrandt
Eric A
EA
Pierce
Nicholas
N
Katsanis
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D000818:Animals; D002925:Ciliary Motility Disorders / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D009154:Mutation; D010375:Pedigree; D010786:Photoreceptor Cells / Q000502:physiology; D015027:Zebrafish / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C528451:Ttc21b protein, mouse
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