#2613 Clinical spectrum and prognosis of the atypical polycystic kidney disease caused by monoallelic loss-of-function IFT140 variants

Abstract

Abstract Background and Aims Monoallelic loss-of-function (LoF) variants in IFT140, which protein product is involved in retrograde ciliary trafficking and ciliary entry of membrane protein, have been recently linked to ADPKD spectrum, with 44 pedigrees reported so far [1]. The aim of this study was to characterize the disease presentation and renal outcome of individuals with monoallelic LoF variants of IFT140. Method Clinical information, family history and imaging data were collected for individuals with LoF IFT140-variants identified amongst 2800 individuals recruited in the Genkyst and Cystic ADPKD patients cohorts, and in different French, Spanish, and German centers. Targeted massive parallel sequencing of cystic genes or whole exome sequencing was performed. Newly identified and recently reported cases were combined to evaluate the influence of sex on eGFR using linear regression taking age into account. In addition, data of the Genome Aggregation (GnomAD) v4.0 and of the 100k Genomes project were respectively used to explore genetic prevalence and disease penetrance and expressivity. Results A total of 75 individuals from 61 pedigrees were identified (median age at last follow-up 56 years, 52% females). Forty-one different LoF IFT140-variants were identified: 14 nonsense, 7 splice-site, 14 frameshifting deletions or insertions and 6 large deletions, and no additional pathogenic variant was identified in any other gene. A majority of the individuals presented with large, exophytic cysts, median total kidney volume 688 (n = 35, range 201-4139) ml, and 90.9% were classified in Mayo Class 2A. Although 70.4% of the individuals had stage 1 or 2 chronic kidney disease (CKD) at the last follow up, proportion of CKD stage 3-5 was significantly higher (56.3% vs 7.7%, p < 0.00001) after 60 years of age. Adjusted for age, males exhibited lower eGFR (linear regression, p = 0.038, Fig. 1). Median age at diagnosis of hypertension was 63 years. Liver cysts were present in 12% of affected individuals with no case of symptomatic polycystic liver disease, and intracranial aneurysms in three of 10 screened patients. The genetic prevalence of monoallelic LoF IFT140 variants was estimated to be 19.56 (0.95 CI 18.60-20.53) per 10,000 in the entire GnomAD population (n = 280 in 807,162) and 29.4 (0.95 CI 25.4-33.8) per 10,000 in the 100kG (n = 190 in 64,185). Amongst the latter, kidney cysts were reported in 26.8% and diagnosis cystic kidney disease (Q61) was established in 18.4%. No obvious extra renal manifestations were identified, and out of total of 730 phenotype association tests conducted, only Q61 was associated with pLOF IFT140 variants (p = 2.9 × 10−9, OR = 5.6 (3.3-9.2)). Conclusion Individuals with monoallelic LoF variants of IFT140 are likely to develop kidney cysts and/or atypical forms of ADPKD. However, a large proportion may remain asymptomatic or undiagnosed. There is no evidence to recommend cascade screening using genetic testing in young at risk relatives. Follow-up of blood pressure and eGFR after 50 years of age should be advised.