Rare multisystem ciliopathy disorders

Gene: IFT81

Amber rating agreed with Genomics England Clinical team: Gene is in the right pathway but 3/4 cases to date have one variant that is not able to be classified as pathogenic/likely pathogenic.

Created: 27 Jun 2019, 8:10 a.m. | Last Modified: 27 Jun 2019, 8:10 a.m.

Panel Version: 1.114

Added watchlist tag.

Created: 20 Jun 2019, 7:59 p.m. | Last Modified: 20 Jun 2019, 7:59 p.m.

Panel Version: 1.106

Comment on list classification: Updated rating from Red to Amber. Associated with OMIM:617895 but not yet associated with a disorder in Gene2Phenotype. Functional data supports a ciliopathy association: IFT81 is part of the IFT-B complex involved in the bidirectional transport of ciliary proteins. Green review from Zornitza based on 3 (or 4) individuals identified in the literature with a Cliopathy phenotype and biallelic IFT81 variants. However in the two cases from PMID:26275418, OMIM classes the variants as VUS. Therefore on balance have classed as Amber awaiting further cases or clarification of the variants in PMID:26275418.

Created: 20 Jun 2019, 7:59 p.m. | Last Modified: 20 Jun 2019, 7:59 p.m.

Panel Version: 1.106

Duran et al. 2016 (PMID:27666822) identify two individuals with skeletal ciliopathies: R98-443 with sphyxiating thoracic dystrophy (ATD), and R13-147A with Short-rib polydactyly syndromes (SRPS). Exome sequencing revealed compound het variants in IFT81 in both cases: p.Leu29Phe and p.Arg512* in R98-443, and p.Leu262* and p.Leu435del in R13-147A.

Created: 20 Jun 2019, 7:55 p.m. | Last Modified: 20 Jun 2019, 7:55 p.m.

Panel Version: 1.105

Perrault et al., 2015 (PMID:26275418) screened 1628 individuals with reno-ocular ciliopathies by sequencing of ciliary candidate genes and identified recessive ITF81 variants in two consanguineous families with a ciliopathy phenotype.
They identified a homozygous variant in IFT81 in one individual (A3286-21) with a nephronophthisis-related ciliopathy, polydactyly and moderate intellectual disability (delayed speech and an IQ of 70). They identified a loss-of-stop variant in IFT81 in a second individual (NCK-033) with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy (RD), brain lesions and mild intellectual disability. The patient also harboured 9 additional rare homozygous variants including a missense change (Gly245Arg) in the gene PPT1, accounting for the clinical diagnosis of neuronal ceroid lipofuscinosis-1. Both these variants have currently been classed as VUS in OMIM.

Created: 20 Jun 2019, 7:54 p.m. | Last Modified: 20 Jun 2019, 7:54 p.m.

Panel Version: 1.105

Green List (high evidence)

I am uncertain which paper the first assessment refers to, but there are 4 unrelated families reported in the literature with ciliopathy phenotypes and variants in this gene, 27666822 also includes functional evidence. I am not completely convinced the second proband in 26275418 had a ciliopathy, but even excluding this case, there is probably sufficient evidence to make this gene Amber if not Green.

Created: 4 Aug 2018, 8:51 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 26275418, 27666822

Variants in this GENE are reported as part of current diagnostic practice

Comment when marking as ready: Variants reported in two patients with features of ciliopathy

Created: 25 Jan 2017, 1:14 p.m.