Second, homozygous null mutations at this locus are responsible for the embryonic lethal alien phenotype in the mouse, a mutant whose anatomical features overlap with some of the severe ciliopathies in humans. First, it encodes a bone fide axonemal protein that is required for retrograde intraflagellar transport. We chose to test this model on TTC21B for several reasons. To test these hypotheses, we have initiated a systematic screening of all genes known to be necessary for ciliary biogenesis and function, coupled to functional assessment of variants detected (irrespectively of their genetically-derived pathogenic potential under a strict Mendelian model). Second, the same loci should contribute epistatic alleles across the same phenotypic spectrum, some of which would be expected to contribute to the severity and/or pleiotropy of the disease. First, if the model outlined above were correct, one would predict that some genes critical to ciliary function would contribute alleles that will appear (genetically) to be necessary and sufficient to cause discrete ciliopathy phenotypes in humans. These observations have raised two possibilities. Recently, epistatic mutations in RPGRIP1L, loss of function of which causes MKS and JBTS, have been shown to modify the penetrance of retinal degeneration across multiple ciliopathies, while an allele in AHI1 can modify retinal phenotypes in individuals with NPHP. Consistent with this notion, mutations in NPHP1-4 have been shown to exacerbate extra-renal phenotypes in NPHP patients with primary lesions at one of the other NPHP genes, whereas mutations in some of the genes that cause MKS can also contribute mutations in patients diagnosed with NPHP, Joubert syndrome (JBTS) - and Bardet-Biedl syndrome (BBS). This integration has also been reflected in the genetic architecture of ciliopathies: although discrete groups of genes and proteins have been causally linked with specific ciliopathies, single-locus allelism has been insufficient to explain the variable penetrance and expressivity of such disorders, leading to the suggestion that genetic variation across multiple sites of the ciliary proteome influences clinical outcome.
The recognition of the clinical overlap between discrete clinical entities attributable to ciliary dysfunction has led to the unification of such disorders under the ciliopathy module. Introduction Genetic and functional studies have recognized that defects in genes encoding components of the ciliary apparatus lead to an overlapping set of clinical phenotypes that include retinal degeneration, renal cystic disease, polydactyly and other skeletal abnormalities, fibrosis of various organs, and a complex range of anatomical and functional defects of the central and peripheral nervous system. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies, as well as 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 disorders. Moreover, although systematic medical resequencing of a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations unmasked a significant enrichment of pathogenic alleles in cases, suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy patients. Here we show that mutations in TTC21B/IFT139, encoding a retrograde intraflagellar transport (IFT) protein, cause both isolated nephronophthisis (NPHP) and syndromic Jeune Asphyxiating Thoracic Dystrophy (JATD). This grouping is underscored by genetic overlap, where causal genes can also contribute modifying alleles to clinically distinct disorders. Ciliary dysfunction leads to a broad range of overlapping phenotypes, termed collectively as ciliopathies.
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