Judy Savige

Autosomal dominant polycystic liver disease (ADPLD) commonly results from pathogenic variants in one of 7 genes ( GANAB, ALG8, ALG9, PRKCSH, SEC63 and possibly LRP5 and SEC61B) . These genes are also included in kidney panels because pathogenic variants cause kidney cysts but rarely kidney failure. This study determined the population frequency of predicted pathogenic variants in the ADPLD genes in the general population. Variants for each gene were downloaded from gnomADv.2.1.1 and annotated with ANNOVAR. The population frequencies were calculated from the number of people with ‘predicted pathogenic’ variants in gnomAD: loss-of-function structural and copy number; null; and rare, computationally-damaging missense changes that affected a conserved residue. Frequencies were also estimated from the number of gnomADv.4.1 variants assessed as Pathogenic or Likely pathogenic in ClinVar. Predicted pathogenic variants affected one in 91 people using our strategy and gnomAD v.2.1.1, and one in 130 with ClinVar assessments of gnomAD v.4.1 variants. LRP5 and ALG8 which are associated with a milder clinical phenotype, were the commonest affected genes with both strategies. Predicted pathogenic variants in ADPLD appear more frequent in admixed American (one in 91), Finnish (one in 110) and African/African American (one in 43) people (p all < 0.0001 compared with Europeans (one in 187). Predicted pathogenic variants for ADPLD may be even more common with the finding of additional causative genes. Assessments will become more accurate too. However not all ADPLD variants result in liver cysts, nor indeed cystic kidneys, because of incomplete penetrance and variable expressivity.

Key Points: We evaluated a hub and spoke mainstreaming model to enable nephrologists to order genomic tests independently in their clinic across the state of Victoria. Over 1000 tests were ordered, with the diagnostic yield remaining similar regardless of ordered by local nephrologists or tertiary genomics services. A mainstreaming model proved feasible, scalable, and clinically effective, offering a practical framework for integrating genomics to routine kidney care. Background: Genomic testing has substantial diagnostic and clinical value in nephrology, yet integrating testing into routine care requires service-level changes to ensure timely and equitable access. Methods: We conducted an observational cohort study at four tertiary centers, with a pragmatic, quasi-experimental design to evaluate evidence-informed, service-level interventions to make genomic testing more accessible and routinely embedded within nephrology practice. We implemented a hub and spoke model which provided nephrologists with training, practical resources, and regular case-based discussions, to support test ordering and interpretation within their own clinics. Laboratory audits (June 2021–July 2024) evaluated how public reimbursement and implementation interventions influenced testing patterns. Three periods were compared: prefunding, postfunding, and postintervention. Results: Across the study period, 1028 genomic tests were ordered (63% adults, 37% children; median age 32 years). Results were available for 1014 tests, with an overall diagnostic yield of 34%, which remained stable across all time points. The diagnostic yield was similar regardless of whether testing occurred at tertiary genomics services (249 of 772, 32%) or via local nephrologists (92 of 242, 38%). The number of unique providers ordering tests was higher (T1: 37, T2: 69, T3: 87). The proportion of testing in mainstream nephrology settings rose from 23% to 74%, while absolute testing numbers in multidisciplinary clinics remained consistent over the study period. Conclusion: Mainstreaming genomic testing in nephrology was feasible, scalable, and clinically effective. This model was associated with better access without compromising diagnostic yield and provides a practical framework for integrating genomic medicine into routine kidney care.

Autosomal dominant Alport syndrome results from heterozygous pathogenic variants in COL4A3 or COL4A4 and is the most common monogenic kidney disease, affecting approximately 1% of the population. It is characterized by persistent glomerular hematuria, a thinned glomerular basement membrane, and a family history of kidney disease. The typical Alport hearing loss and ocular abnormalities are not present. Autosomal dominant Alport syndrome is common in cohorts with hematuria, proteinuria, steroid-resistant nephrotic syndrome, kidney cysts, or kidney failure. Clinical features vary even in family members with the same genetic change. Overall, only two thirds of people with a heterozygous pathogenic COL4A3 or COL4A4 variant have hematuria because of incomplete penetrance. Missense variants that result in Gly substitutions are associated with proteinuria more often than truncating changes, which is different from X-linked disease. However missense variants are not consistently associated with kidney failure or the age at kidney failure. Sometimes, genetic testing is negative even where clinicians strongly suspect autosomal dominant Alport syndrome. Genetic testing distinguishes autosomal dominant Alport syndrome from X-linked disease, which is less common but has a higher risk of kidney failure. Autosomal dominant Alport syndrome with more severe features must also be distinguished from digenic disease especially where only one of the two causative variants is identified. People with autosomal dominant Alport syndrome should be monitored for increased albuminuria and treated from its onset with angiotensin-converting enzyme inhibitors and, if necessary, sodium-glucose cotransporter 2 inhibitors. Genetic testing is currently recommended for all first-degree family members whether or not they have hematuria.

Background: Renal imaging suggests that congenital anomalies of the kidney and urinary tract (CAKUT) affect one in 200 of the population, and 20% have a monogenic cause. This study determined the population frequency of predicted pathogenic variants in six commonly affected CAKUT genes. Methods: HNF1B , SALL1 , EYA1 , PBX1 , GATA3 , and PAX2 variants were downloaded from gnomAD v.2.1.1 ( n = 141,456) and the population frequency of predicted disease-causing variants calculated from the sum of structural, null, and predicted pathogenic missense changes in the overall cohort or from variants shared with ClinVar, HGMD, or LOVD. Population frequencies were also determined in constituent ancestries and, using our method and ClinVar assessments, in a replication cohort (gnomAD v.4.1, n = 807,162). Results: The population frequency of disease-causing variants in these six genes in CAKUT lies between one in 249 (our strategy) and one in 1263 (ClinVar assessments) in the gnomAD v.2.1.1 database. More than half these variants were missense changes. Predicted pathogenic variants were commonest in African-Americans (one in 149) and least common in Ashkenazim (one in 864). The population frequency estimated from gnomAD v.4.1 lies between one in 372 (our strategy) and one in 1,762 (with ClinVar). Conclusions: These calculations suggest that monogenic causes of CAKUT due to variants in these six genes are likely more common than the previously calculated one in 1,000. The ClinVar results are underestimates since assessments were not available for structural, copy number and many missense changes. However, some disease-causing variants identified here will not result in clinical disease because of incomplete penetrance and variable expressivity. Graphical

Genetic disease is often unrecognised. This study examined how often renal clinic patients, with a non-genetic diagnosis and without a family history of genetic disease recorded at the last three visits, had an underlying genetic form of kidney disease or diabetes. Sixty-four consecutive unrelated patients from a general nephrology clinic (44 male, 20 female) with a median age of 66 years (range 26 – 87) underwent chart review and Whole Exome Sequencing (WES). WES results were filtered for rare disease-causing single nucleotide and copy number variants in genetic kidney disease (n = 495) and monogenic diabetes (n = 8) genes. The patients’ diagnoses included diabetes (n = 36, 56%), diabetic kidney disease (n = 28, 44%), autoimmune glomerulonephritis (n = 20,31%) or others (n = 12, 19%). Six (9%) volunteered a family history of genetic disease at recruitment. Twenty had at least one kidney cyst on imaging (20/59, 34%). Forty-four (69%) had an eGFR between 20 and 60 ml/min/1.73m², and 14 (22%) an eGFR < 20 ml/min/1.73m² or had undergone renal replacement therapy. Seven Pathogenic or Likely pathogenic variants (according to ClinVar) were found in 7 people (11%), in COL4A3, CFH, and CHD7, and 3 cystic kidney genes (PKHD1 (n = 2), SEC63, LRP5). Three further individuals with diabetic kidney disease (3/36, 8%) had a possibly pathogenic variant (Likely pathogenic in one, and VUS in 2, in ClinVar) in a monogenic diabetes gene (HNF1A, ABCC8, NEUROD1). Pathogenic variants in a gene associated with kidney disease were identified in only three of the 6 patients with a positive family history. In conclusion, genetic variants associated with monogenic kidney disease occurred in possibly 11% (7/64) of renal clinic patients with a non-genetic diagnosis, and variants associated with monogenic diabetes in a further 9% (3/36) with diabetic kidney disease.

Autosomal polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease. The international guideline developer, Kidney Disease: Improving Global Outcomes (KDIGO), published a 2025 clinical practice guideline reflecting advances in genetic testing and the first disease‐modifying agent, tolvaptan. However, KDIGO guidelines do not address healthcare access or equity issues relevant to the needs of our populations in Australia and New Zealand. The Caring for Australians and New ZealandeRs with kidney Impairment (CARI) Guidelines Working Group has provided a regional commentary to contextualise the KDIGO 2025 ADPKD guideline. This commentary aims to support clinicians in applying the KDIGO ADPKD 2025 guidance within our local health systems and highlights challenges in the implementation, including public subsidy limitations for recommended genetic testing and treatments. It also addresses equity concerns such as rural and remoteness, ensuring guidance is relevant to Australia and New Zealand.

Autosomal dominant polycystic liver disease (ADPLD) commonly results from a pathogenic variant in one of 6 genes (GANAB, ALG8, LRP5, PRKCSH, SEC61B, SEC63). Pathogenic variants in these genes are also associated with kidney cysts, which rarely cause kidney failure, but the genes are included in cystic kidney panels. This study determined the population frequency of predicted pathogenic variants in the ADPLD genes in the general population. Variants for each gene were downloaded from gnomAD and annotated with ANNOVAR. The population frequencies were calculated from the number of people with "predicted pathogenic" variants in gnomAD v.2.1.1:loss-of-function structural and copy number; null; and rare, computationally-damaging missense changes that affected a conserved residue. Frequencies were also estimated from the number of gnomADv.4.1 variants assessed as Pathogenic or Likely pathogenic in ClinVar. Predicted pathogenic variants affected one in 95 people using our strategy and gnomAD v.2.1.1, and one in 151 with ClinVar assessments of gnomAD v.4.1 variants. LRP5 and ALG8 which are associated with a milder clinical phenotype, were the commonest affected genes with both strategies. Predicted pathogenic variants in ADPLD appear more frequent in admixed American (one in 100), Finnish (one in 107) and African/African American (one in 130) people (p all <0.0001 compared with Europeans (one in 197).Predicted pathogenic variants for ADPLD may be even more common because of additional unidentified causative genes. However not all ADPLD variants result in liver cysts, nor indeed cystic kidneys, because of incomplete penetrance and variable expressivity.

Up to 20% of people with clinically suspected Alport syndrome do not have a disease-causing variant identified with genetic testing. Disease-causing changes are ‘missing’ because the identified variant is of uncertain significance or no suspicious change has been found. A variant of uncertain significance might be resolved after a clinician–laboratory consultation, family segregation studies, functional assays, evidence from large case–control cohorts or review after further genetic and experimental information becomes available. Other explanations for a lack of disease-causing variants include the presence of phenocopies such as IgA nephropathy, technical issues associated with whole-exome sequencing and difficulties in identifying and computationally assessing non-canonical splicing variants, including deep intronic and synonymous changes. Candidate splicing variants might be identified using whole-exome, whole-genome or long-read sequencing, prioritized bioinformatically, and validated with targeted RNA sequencing or splicing assays. People with suspected Alport syndrome but no identified disease-causing variant should be managed as for Alport syndrome while awaiting confirmation of their diagnosis. Missing disease-causing variants are also common in other genetic kidney diseases, and the methods used for their resolution are the same. Our current inability to detect all disease-causing variants means that the contribution of genetic disease is underestimated for kidney phenotypes.