Journal
NATURE GENETICS
Volume 43, Issue 3, Pages 189-U28Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.756
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Funding
- US National Institutes of Health [R01HD04260]
- National Institute of Child Health and Development [R01DK072301, R01DK075972, R01DK068306, R01DK064614, R01DK069274]
- National Institute of Diabetes, Digestive and Kidney disorders [F32 DK079541]
- National Eye Institute [RO1EY12910]
- Macular Vision Research Foundation
- Foundation Fighting Blindness
- F.M. Kirby Foundation
- Rosanne Silbermann Foundation
- Polycystic Kidney Disease (PKD) Foundation
- German Kidney Foundation
- German Research Foundation (DFG) [BE 3910/5-1, SFB/TRR57]
- UNADEV
- Retina France
- Programme Hospitalier de Recherche Clinique
- L'Agence nationale de la recherche
- Medical Research Council (MRC)
- National Human Genome Research Institute
- MRC [G0601347, G0801843, G9901217, G0700073] Funding Source: UKRI
- British Heart Foundation [RG/10/13/28570] Funding Source: researchfish
- Medical Research Council [G0700073, G0601347, G9901217, G0801843] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [09JTA] Funding Source: researchfish
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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 similar 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.
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