Submission Details

The IFT140 gene was first reported in relation to autosomal recessive cases of Mainzer-Saldino syndrome or the clinically overlapping Jeune syndrome in 2012 (Perrault et al., PMID: 22503633). Affected individuals with causal biallelic variants in IFT140 have since been identified in a number of other publications, with syndromic cases most often referred to as short-rib thoracic dysplasia 9 with or without polydactyly (PMID: 23418020), and non-syndromic cases typically diagnosed with Leber congenital amaurosis or retinitis pigmentosa 80 (PMID: 26216056). Both groups of patients generally present in infancy or childhood with retinal dystrophy phenotypes such as night blindness, central vision loss, peripheral visual field loss, retinal arteriolar constriction, undetectable electroretinogram, pigmentary retinopathy, and loss of photoreceptors in the inner and outer segments. The subset of patients with syndromic presentations additionally exhibit skeletal abnormalities that can include cone-shaped epiphyses of the hands and feet, Type A brachydactyly, short stature, and narrow thorax with short, thickened ribs that can lead to respiratory insufficiency. These cases can also exhibit morphological abnormalities of the kidney such as renal cysts and reduced renal corticomedullary differentiation that can progress to renal insufficiency, as well as functional abnormalities of the liver such as cholestasis. Some of the causal IFT140 variants overlap between cases with different diagnoses, and a single affected family can include both ocular and syndromic cases (PMID: 26359340). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found the molecular mechanism (biallelic loss of function in the IFT140 gene product) and mode of inheritance (autosomal recessive) to be consistent among unrelated patients diagnosed with either short-rib thoracic dysplasia 9 with or without polydactyly (MIM#: 266920), Leber congenital amaurosis, or retinitis pigmentosa 80 (MIM#: 617781). The phenotypic variability between them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, these cases have been lumped into a single disease entity, referred to as IFT140-related recessive ciliopathy (MONDO:0100509). An additional disease entity, autosomal dominant polycystic kidney disease (ADPKD), has been asserted in relation to monoallelic variants in IFT140 (PMID: 34890546). While this phenotype is characterized by some similar clinical characteristics and overlapping variants, its different mode of inheritance, incomplete penetrance, and absence of a consistent ocular phenotype raised the possibility of a different mechanism of pathogenesis. Thus, IFT140 has been separately curated for its relationship to this disease entity, referred to as ADPKD-IFT140.

Fourteen suspected pathogenic variants in IFT140 were scored as part of this curation (seven missense, five frameshift, and two affecting splicing), which have been collectively reported in eight probands in three publications (PMID: 22503633, PMID: 23418020, PMID: 26216056). One proband was homozygous for the missense variant of interest and was reported to have consanguineous parents (PMID: 22503633). The other seven probands were compound heterozygotes within the IFT140 locus (PMID: 22503633, PMID: 23418020, PMID: 26216056). One family with segregation evidence was available in these publications (PMID: 22503633), but it included too few affected individuals to contribute to the scoring of the gene-disease relationship. More case-level data was available (PMID: 26359340, PMID: 23418020), but was not scored as part of this curation as the maximum scoring for this evidence type had already been reached.

The mechanism of pathogenicity appears to be biallelic loss of function, characterized in some cases by frameshift or splicing variants predicted to trigger a decrease in the amount of the gene product (PMID: 22503633, PMID: 23418020, PMID: 26216056). All probands found for this curation harbored two variant alleles within the IFT140 locus, with many harboring a missense variant in trans with a predicted loss-of-function variant, and none harboring a predicted loss-of-function variant in the homozygous state.

This gene-disease association is also supported by experimental evidence that IFT140 encodes one of the components of intraflagellar transport sub-complex A, which functions in retrograde transport in the cilia (PMID: 20889716), a process that is required for axonemal growth. This role implies that the disease entity caused by IFT140 loss-of-function variants is a ciliopathy, and matches the finding that IFT140 expression reaches its highest levels within human tissues that contain multiciliated cells, including thyroid, testis, fallopian tube, pituitary gland, ovary, and lung tissues (PMID: 23715323). This function is consistent with the cellular characteristics of patient tissues, which can include a reduced proportion of ciliated cells (PMID: 22503633) and shortened cilia with swollen tips (PMID: 29706353). These cellular features are recapitulated by both Chlamydomonas (PMID: 28207750) and mouse (PMID: 30479745) cellular models of IFT140 loss of function. Rescue experiments indicate that these cellular phenotypes can be reversed in patient cells subjected to CRISPR/Cas9-based correction of an endogenous IFT140 variant (PMID: 29706353). While homozygous Ift140 knockout mice show embryonic lethality, mice harboring homozygous missense mutants with incomplete loss of Ift140 function recapitulate human patient phenotypes such as rib cage and digit anomalies, disruption of eye development, and severe morphological anomalies of primary cilia in the limb buds (PMID: 24009529).

In summary, IFT140 is definitively associated with IFT140-related recessive ciliopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification. This classification was approved by the ClinGen Retina GCEP on July 7th, 2022 (SOP Version 9).