#1723 Genetic landscape of polycystic kidney disease in a Chinese cohort – experience using whole genome sequencing in a tertiary renal unit
Authors: MA Becky Mingyao , Kwok Jamie Sui Lam , Tam Helen Ying Fung , Or Dicky , Hue Shirley Pik Ying ,   Hong Kong Genome Project, Chu Annie Tsz Wai , Chan Gary Chi Wang , Kwan Pui Yuen Lorraine , Yap Desmond , Choy Bo Ying , Chung Brian Hon Yin 
Published: May 2024

Abstract

Background and Aims
Genetic testing has increasingly been employed to provide definitive diagnoses and prognostic information in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). We aim to explore the genetic landscape of ADPKD in a Chinese cohort utilizing whole genome sequencing and study its real-world clinical utility.

Method
From 1st January 2022 to 31st March 2023, we recruited 50 adult Chinese patients who had the clinical diagnosis of ADPKD followed up at Queen Mary Hospital and consented to the study protocol. The study was approved by the University Institution Review Board and local ethics committees. Genomic DNA was isolated from samples obtained from patients per standard protocol. Whole-genome sequencing was performed and analysed through the germline analysis pipeline. Diagnostic analysis was performed per American College of Medical Genetics (ACMG) guidelines and ClinGen variant curation expert panel specifications. Diagnostic variants were defined as those classified as ‘pathogenic’ or ‘likely pathogenic’. Potential clinical utility of genetic findings were studied case-by-case based on the Kidney Disease Improving Global Outcomes (KDIGO) 2023 Clinical Practice Guideline for the Evaluation, Management and Treatment of ADPKD.

Results
Among the 50 unrelated probands with ADPKD, half were males and the mean age at presentation was 38. 38% patients had incidental finding of kidney cysts on abdominal imaging performed for unrelated symptoms or health screening, 32% presented for screening due to positive family history and only 30% presented with typical symptoms of ADPKD. Cystic complications were present in 30%, with cyst haemorrhage being the most common, followed by kidney stones, cyst rupture and infection. 80% patients also had liver cysts and none had a history of cerebral aneurysms. The majority of our cohort (72%) had a family history of ADPKD.
We identified diagnostic variants in 35 individuals, reaching a diagnostic yield of 70%. Diagnostic variants were identified in PKD1 (20/35), PKD2 (11/35), IFT140 (3/35) and ALG9 (1/35). The majority of diagnostic variants were protein-truncating (32/35), while non-truncating variants consisted of 1 in-frame deletion and 2 missense variants in PKD1. We identified 3 copy number variation:NC_000016.10:g.2110587_2111851del,NC_000016.10:g.2132339_2137621del,NC_000016.10:g.2036427_2101117del.
The genetic findings allowed physicians to make definitive diagnosis in 9 patients with negative family history of ADPKD. The genetic findings provided important prognostic information as protein-truncating variants in PKD1 or PKD2 were associated with more severe disease compared to non-truncating variants. For the 3 patients harbouring heterozygous pathogenic variants in IFT140 (NM_014714.4:c.2659G&gt;T, NM_014714.4:c.3780del, NM_014714.4:c.1035_1036del), they demonstrated a milder PKD phenotype with stable kidney function, normal kidneys size and absence of liver cysts 10 years after the diagnosis. The patient with heterozygous likely pathogenic ALG9 variant (NM_024740.2:c.1225del) also had milder PKD phenotype with normal kidney function and normal sized kidneys on USG 5 years after the diagnosis. In another male patient with young hypertension who was classified as Mayo Class 1C according to kidney imaging, identifying the pathogenic protein-truncating variant in PKD1 (NM_001009944.3:c.7288C&gt;T) would render him eligible to tolvaptan treatment in view of the high PROPKD score (7). Furthermore, the genetic findings enabled an earlier diagnosis in a number of family members by cascade testing and genetic results were important to identify suitable living-related kidney donors.

Conclusion
Genetic testing utilizing whole genome sequencing has multiple clinical utility in ADPKD patients. It could provide a definitive diagnosis in those with atypical presentation or without family history, inform prognosis, guide treatment, determine living-related donor suitability and allow earlier diagnosis in other family members.