IFT140

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0100509

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0100509

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0002473

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0100509

Submitter: Illumina

Inheritance Pattern: AD

Disease ID:MONDO:0004691

Submitter: ClinGen

*IFT140* was first reported in relation to autosomal dominant polycystic kidney disease (ADPKD) in 2021 (Senum et al., PMID: 34890546). Biallelic *IFT140* variants are causative in an autosomal recessive ciliopathy (OMIM: 266920), and have been curated as a separate gene-disease relationship. The proximity of *IFT140* and PKD1 on chromosome 16 could lead to diagnostic confusion because of co-segregation in families and with PKD1 variants possibly modifying the *IFT140* phenotype. However, there is strong evidence that *IFT140*, on its own, can cause kidney and liver cysts. More than 30 variants have been reported in individuals with renal cysts in 3 publications. Sixteen variants (nonsense, frameshift, and splice site) from 3 publications are included in this curation (PMIDs: 34890546, 37844724, 38404363). The distinctive monoallelic phenotype is a cystic kidney phenotype, of ranging severity, with large cysts, usually preserved kidney function, varying prevalence of hypertension, and, in some cases, liver cysts. Chronic kidney disease is usually mild and does not progress to end-stage kidney disease. This gene-disease relationship has been studied in 1 case-control study (Senum et al.) at the aggregate variant level with an OR of 12.81. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be haploinsufficiency. This gene-disease relationship is also supported by experimental evidence, in the form of a mouse model (Jonassen et al., PMID: 22282595). This gene-disease pair was originally evaluated by the ClinGen Kidney Cystic & Ciliopathy GCEP on 4/15/2022. It was re-evaluated on 3/11/2024. As a result of this reevaluation, the classification increased from Strong to Definitive with the addition of genetic evidence (PMIDs: 37844724, 38404363). In summary, there is Definitive evidence supporting the relationship between *IFT140* and an autosomal dominant kidney cystic phenotype. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic & Ciliopathy Gene Curation Expert Panel (GCEP) on the meeting date 3/11/24 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0009964

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0054708

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: Natera

Inheritance Pattern: AD

Disease ID:MONDO:0004691

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0009964

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0004691

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0018770

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009964

Submitter: G2P