Kidney Week 2025 Annual Meeting-Revisiting Mendelian Kidney Diseases: Understanding Phenotype Variability

Video Transcription

Video Summary

The session “Revisiting Mendelian Kidney Diseases: Understanding Phenotypic Variability” opened with moderators Mark Elliott and Erica Davis introducing talks focused on why monogenic kidney disorders show wide differences in severity and outcomes.<br /><br />Dr. LaKia (UT Southwestern) reviewed variable disease severity in autosomal dominant polycystic kidney disease (ADPKD). She emphasized both interfamily and intrafamily variability, supported by cohort studies showing measurable discordance among relatives. Understanding this variability improves counseling, prognostication (Mayo Imaging Classification, PRO-PKD score, genetic testing), therapy selection (e.g., tolvaptan eligibility), and clinical trial design. She outlined genotype–phenotype relationships: PKD1 truncating variants tend to cause earlier kidney failure than PKD1 non-truncating variants, with PKD2 generally milder and later onset. Mutation location within PKD1 may also influence progression. She highlighted special genetic mechanisms (hypomorphic alleles, biallelic effects, mosaicism), polygenic risk contributions, and non-genetic modifiers such as male sex, obesity, hypertension, diabetes, and hyperlipidemia.<br /><br />Dr. Shuying Lin (Mayo Clinic) presented zebrafish models to identify genetic modifiers of cystic kidney disease. Zebrafish enable higher-throughput functional testing than rodents. Using IFT140 embryonic cyst readouts and CRISPR-based approaches, her group screened candidate pathways and validated modifiers (e.g., mTOR). Adult zebrafish models, including a PKD1 knock-in mimicking a human pathogenic variant, allow testing of modifiers affecting kidney cysts and potentially cardiac dysfunction.<br /><br />A talk from the Alport Syndrome Foundation described evolving genotype-based classification of Alport syndrome, shifting away from “benign hematuria/thin basement membrane disease” terminology and emphasizing variant type and location as key predictors of severity.<br /><br />Dr. Rick Westland (Amsterdam) addressed CACUT heterogeneity and low diagnostic yield, arguing for multi-omics fetal kidney atlases, improved prenatal prognostic biomarkers (e.g., amniotic peptidomics in posterior urethral valves), and large collaborative cohorts integrating genetics, environment, and clinical data.

Asset Subtitle

Moderator(s): Erica Davis, Mark Elliott

Presentation(s):

Understanding Variable Disease Severity in ADPKD - Ronak Lakhia
Identification of Genetic Modifiers of Cystic Kidney Diseases Using Zebrafish - Xueying Lin
Phenotypic Variability in Alport Kidney Diseases: Current State of Genotype-Phenotype Correlation - B. Andre Weinstock
Strategies to Overcome Clinical and Genetic Heterogeneity in Congenital Anomalies of the Kidney and Urinary Tract - Rik Westland

Meta Tag

Date 11/7/2025

Pathway 1 Genetic Diseases and Development

Session ID 507041

Keywords

Mendelian kidney diseases

phenotypic variability

monogenic kidney disorders

autosomal dominant polycystic kidney disease

ADPKD

PKD1 truncating variants

PKD2 genotype-phenotype

Mayo Imaging Classification

PRO-PKD score

tolvaptan eligibility

genetic modifiers

zebrafish models

CRISPR screening

Alport syndrome genotype-based classification

congenital anomalies of the kidney and urinary tract (CACUT)