IFT57

Inheritance Pattern: AR

Disease ID:MONDO:0054770

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

The *IFT57* gene is located on chromosome 3 at 3.q13.12-q13.13 and encodes the Intraflagellar Transport Protein 57 (*IFT57*). This protein is essential for cilia assembly and function and plays a crucial role in intraflagellar transport. *IFT57* is part of a complex that connects IFTB to the motor protein kinesin 11. IFTB initiates the polymerisation process and IFTA then joins to complete the train. *IFT57* is also implicated in apoptosis and signalling pathways including the sonic hedgehog pathway. *IFT57* is expressed at high levels in the lung and testis, and at low levels in the kidney cortex and medulla, where it is found mainly in the proximal tubule. *IFT57* has only been reported associated with Orofaciodigital syndrome XVIII (OMIM:617927), which has autosomal recessive (AR) inheritance, and is considered an overlap of Orofaciodigital syndrome and Ellis-van Creveld syndrome. This disorder has variable if any kidney involvement but was included in this GCEP’s assessment because it is a ciliopathy.The GCEP-preferred disease name suggested for this disorder is ? Orofaciodigital syndrome XVIII (OMIM:617927) or Ciliopathy-*IFT57*. *IFT57* was first reported in relation to AR Orofaciodigital syndrome XVIII in 2016 (Thevenon et al, PMID: 27060890). The mechanism of pathogenicity is reported as Loss of Function. Clinical features include mainly facial, oral and digital anomalies. Short stature, limb shortening, congenital cardiac anomalies, retinal disease, midline high arched palate, cleft palate, cleft or lobulated tongue, cleft lip, dysplastic nails and teeth, oral frenulae, polydactyly and genu valgum may be present. Hearing, speech and intellect are normal. Kidney and urinary tract abnormalities are very variable, with urinary incontinence in one person, a short urethra in another person, increased urinary albuminuria (associated with diabetes) and normal kidney imaging. At least three variants (a homozygous splicing variant in 2 offspring of a consanguineous Indian family; and a compound heterozygous variant in an Irish male with a missense and a frameshift change) have been reported in three probands in two publications (PMID:27060890; PMID:40273360) that are included in this curation. Additional genetic evidence for the homozygous splicing variant was the functional impact of this variant on ciliary transport, with low *IFT57* staining mainly in the ciliary bases compared with controls; the same number of cilia but decreased ciliary tip staining; reduced anterograde transport in the subject’s fibroblasts; and reduced GLI1 transcription activation secondary to less sonic Hedgehog signalling pathway in patient fibroblasts compared with healthy controls. The compound heterozygous variants when expressed in fibroblasts had fewer ciliated cells and more abnormal cilia than controls. A total of 4.6 points for genetic evidence was reached. This gene-disease relationship is also supported by expression (PMID:27060890), interaction with IFT172 (PMID:40273360) and functional alteration where an *IFT57* variant resulted in decreased ciliary anterograde transport in a patient-derived fibroblast cell line (PMID: 207060890). The cell culture system demonstrated that *IFT57* Val397Glu resulted in reduced binding of *IFT57*, *IFT172* and *IFT88* to the IFTB complex that impaired anterograde transport (PMID: 40273360). Partial rescue occurred with the administration of expression vectors with the ift57Val397Glu variant to a mouse ift57 gene knockout cell line (derived from mouse medullary collecting duct cells, PMID:40273360). This was in contrast with rescue with the ift57 wildtype (PMID:40273360). A total of 4 pts for experimental evidence was reached. In summary, there is moderate evidence supporting the relationship between *IFT57* and AROrofaciodigital syndrome. This has been demonstrated in both the research and clinical diagnostic settings and has been upheld over time.This classification was approved by the ClinGen Kidney Cystic and Ciliopathy GCEP on the meeting date 11 August 2025 (SOP Version 11).

Inheritance Pattern: Unknown

Disease ID:MONDO:0054770

Submitter: Labcorp Genetics (formerly Invitae)