Skeletal dysplasiaGene: IFT81
other forms of short-rib dysplasia are listed in Cilliopathies with major skeletal involvement gp of SDs. Only 2 cases reported?; Review on behalf of Tracy Lester
Created: 6 Mar 2019, 11:44 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Short-rib thoracic dysplasia 19 with or without polydactyly -617895
Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM
PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512*. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components
PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly (c.1188+1G-A). The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. Only candidate gene sequencing of IFT-B complex proteins was found. A variant in IFT81 (c.2015_2019delACCGG) was also found in a second unrelated child with retinal dystrophy and intellectual disability (no skeletal phenotype) suggestive of a ciliopathy however 9 additional rare homozygous variants were found and so this variant has also been classified as a VUS in OMIM.
PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband.
PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples.
Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype and the variant classified as a VUS. 4th case with tandem duplication of 2 exons which is predicted to result in a truncated protein.
Created: 16 Jul 2019, 12:41 p.m. | Last Modified: 31 Jul 2019, 2:22 p.m.
Panel Version: 1.192
Additional publication - PMID: 30080953 Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples.
Created: 7 May 2019, 9:34 p.m. | Last Modified: 31 Jul 2019, 2:05 p.m.
Panel Version: 1.192
This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: IFT81; Initial rating suggestion: amber
Created: 6 Mar 2019, 11:36 a.m.
Publications for gene: IFT81 were set to 27666822; 26275418; 28460050
Added phenotypes Short-rib thoracic dysplasia 19 with or without polydactyly -617895 for gene: IFT81 Publications for gene IFT81 were changed from 26275418; 28460050; 27666822 to 27666822; 26275418; 28460050
Source NHS GMS was added to IFT81. Rating Changed from Green List (high evidence) to Green List (high evidence)
This gene has been classified as Green List (High Evidence).
IFT81 was added to Unexplained skeletal dysplasiapanel. Sources: Other
IFT81 was created by arianna