Challenging Disease Ontology by Instances of Atypical PKHD1 and PKD1 Genetics

Abstract

BackgroundAutosomal polycystic kidney disease is distinguished into dominant (ADPKD) and recessive (ARPKD) inheritance usually caused by either monoallelic (PKD1/PKD2) or biallelic (PKHD1) germline variation. Clinical presentations are genotype-dependent ranging from fetal demise to mild chronic kidney disease (CKD) in adults. Additionally, exemptions from dominant and recessive inheritance have been reported in both disorders resulting in respective phenocopies. Here, we comparatively report three young adults with microcystic-hyperechogenic kidney morphology based on unexpected genetic alterations beyond typical inheritance.MethodsNext-generation sequencing (NGS)-based gene panel analysis and multiplex ligation-dependent probe amplification (MLPA) of PKD-associated genes, familial segregation analysis, and reverse phenotyping.ResultsThree unrelated individuals presented in late adolescence for differential diagnosis of incidental microcystic-hyperechogenic kidneys with preserved kidney and liver function. Upon genetic analysis, we identified a homozygous hypomorphic PKHD1 missense variant causing pseudodominant inheritance in a family, a large monoallelic PKDH1-deletion with atypical transmission, and biallelic PKD1 missense hypomorphs with recessive inheritance.ConclusionBy this report, we illustrate clinical presentations associated with atypical PKD-gene alterations beyond traditional modes of inheritance. Large monoallelic PKHD1-alterations as well as biallelic hypomorphs of both PKD1 and PKHD1 may lead to mild CKD in the absence of prominent macrocyst formation and functional liver impairment. The long-term renal prognosis throughout life, however, remains undetermined. Increased detection of atypical inheritance challenges our current thinking of disease ontology not only in PKD but also in Mendelian disorders in general.

Mutation Analysis of <i>PKD1</i> and <i>PKD2</i> Genes in a Large Italian Cohort Reveals Novel Pathogenic Variants Including a Novel Complex Rearrangement

“…Although it is reasonable to speculate that patients with mild disease and those without an established familial history (more than 50% of unsolved patients in our cohort are sporadic) escaped an early clinical observation, it is also possible that in some patients with a family history, we missed the causative mutation. About this, we cannot rule out the presence of mutations in additional genes besides PKD1 and PKD2 (i.e., GANAB , HNF1b , DNAJB11 , PRKCSH, ALG8 , PKHD1 ) which have rarely been found in association with atypical or milder forms of ADPKD or, in addition to variants in the main two genes, worsened the clinical picture, likely by reducing the polycystin dosage [18, 34, 39, 55, 56]. Notably, in 17 out of 26 unsolved patients, we sequenced the GANAB gene without finding any pathogenic variants (not shown).…”

Validation of the ACMG/AMP guidelines-based seven-category variant classification system

“…Keyword searches in PubMed using "PKD1" plus "homozygote", "incomplete penetrant", "hypomorphic", "biallelic" or "trans heterozygous" identified further studies reporting PKD1 "hypomorphic" variants [44][45][46][47][48][49]. Notably, the Durkie study reported a high prevalence of biallelic inherited "hypomorphic" PKD1 variants in very early onset PKD [48].…”