Heterozygous loss of function variants in IFT140 are associated with polycystic kidney disease.

Autor: Clark D; Natera, Inc., Austin, Texas, USA., Burns R; Natera, Inc., Austin, Texas, USA., Bloom MS; Natera, Inc., Austin, Texas, USA., Lim KPH; Natera, Inc., Austin, Texas, USA., Li L; Natera, Inc., Austin, Texas, USA., Vincent LM; Natera, Inc., Austin, Texas, USA., Xie J; Natera, Inc., Austin, Texas, USA., Xue Y; Fulgent Genetics, Temple City, California, USA., Punj S; Natera, Inc., Austin, Texas, USA.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2024 Dec; Vol. 194 (12), pp. e63841. Date of Electronic Publication: 2024 Aug 13.
DOI: 10.1002/ajmg.a.63841
Abstrakt: Autosomal dominant polycystic kidney disease (ADPKD) affects 1 in 1000 adults. Most cases result from causative PKD1 or PKD2 variants. HNF1B, GANAB and ALG9 variants are also associated with ADPKD. Recent evidence indicates that monoallelic loss-of-function (LoF) IFT140 variants are a cause for non-syndromic ADPKD. We describe 368 patients with IFT140 LoF variants and a spectrum of phenotypic findings that support the association of IFT140 with PKD. We reviewed patients with an unknown cause for their cystic disease and those with heterozygous LoF IFT140 variants classified as pathogenic or likely pathogenic from a cohort that received genetic testing using a panel of 385 renal disease-associated genes. IFT140 LoF variants were significantly enriched in patients with cystic disease when compared with those without cystic disease. A cystic phenotype was reported in 223 of the 368 (60.6%) individuals harboring an IFT140 LoF variant, 98% of which had no other identified cause for their cystic disease. Of 122 unique LoF IFT140 variants identified, 56 (46%) were frameshift, 38 (31%) nonsense, 22 (18%) splice site and 6 (5%) exon-level deletions. Only six IFT140 individuals were reported with end-stage kidney disease, consistent with observed milder clinical presentations in IFT140-related PKD. This study offers further evidence for the involvement of LoF IFT140 variants in PKD, particularly when no additional molecular etiology has been identified.
(© 2024 Natera Inc. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
Databáze: MEDLINE
Externí odkaz: