Lessons From the Clinic: ADPKD Genetic Test Unraveling Severe Phenotype, Intrafamilial Variability, and New, Rare Causing Genotype

Abstract

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Co-Inheritance of Pathogenic Variants in PKD1 and PKD2 Genes Determined by Parental Segregation and De Novo Origin: A Case Report

“…The variant occurring de novo in the proband is predicted to cause nonsense mediated decay (NMD) and was classified as “likely pathogenic” according to ACMG guidelines [ 38 ]. This additional finding is in accordance with the speculation that the most severe clinical course might be associated with a more complex genotype, thus underlining the importance of genotyping in the presence of pedigree with relevant clinical variability [ 31 ].…”

“…However, the clinical spectrum of both renal and extrarenal manifestations of the disease, in terms of age at diagnosis, renal survival and complications, is often significantly variable among affected individuals, even within a single family [ 3 , 4 , 30 ]. Intra- and inter-familial disease severity reportedly ranges from onset in prenatal/neonatal period in very early onset ADPKD (ADPKD VEO ) and before the age of 15 years in early onset ADPKD (ADPKD EO ) to elderly patients with preserved kidney function [ 31 ]. Pathogenic variants in PKD1 are typically associated with earlier onset and more severe disease than in PKD2- patients, with an average age at ESRD of 54 in PKD1 -related ADPKD, versus 74 years in PKD2 -related disorders [ 2 , 5 ].…”

Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of PKD1 Hypomorphic Alleles

“…In order not to overestimate the true frequency of hypomorphic variants, we also excluded patients with a de novo PKD1 variant in which the phase was not known. Some studies also reported biallelic PKD2 variants or digenic PKD1/PKD2 inheritance [ 12 , 13 , 14 ]: for the sake of this article, we decided to exclude these patients, focusing on PKD1 variants only.…”

“…Furthermore, ADPKD can be caused by a de novo variant in sporadic cases, but some patients were found to carry biallelic PKD1 variants, inherited from healthy or mildly affected parents; these variants acted as hypomorphic or reduced-penetrance alleles [ 11 ]. Occasionally, digenic inheritance has also been described, with patients carrying a trans-heterozygous pathogenic allele in PKD2 and a hypomorphic variant in PKD1 [ 12 , 13 , 14 , 15 ].…”

Familial Variability of Disease Severity in Adult Patients With ADPKD

“… 3 , 6 , 7 Although ADPKD is well-known for its familial variability, it remains incompletely understood, 8 , 9 though it can be explained for a small subset of cases. 10 , 11 , 12 , 13 Also, in a large ADPKD cohort, the prevalence estimate of the marked intrafamilial variability in disease severity was reported as at least 12%. 14 Based on clinical progression and total kidney volume (TKV), the same group found 18% of patients with PKD1 protein-truncating (PT) variant, who had a poor prognosis, had a less severe kidney phenotype, suggesting modifying factors that may accelerate or slow disease progression.…”