INTRAFAMILIAL VARIABILITY OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE: A SERIES OF CASE REPORTS

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disorder, with a prevalence of 4–6.8 per 10,000 individuals, and the third leading cause of end-stage renal disease (ESRD). ADPKD is primarily caused by mutations in the PKD1 and PKD2 genes. The disease prognosis is also variable: development of terminal ESRD can occur in both older age and earlier stages. It is assumed that modifier genes, polygenic background, and complex genotypes (e.g., digenic inheritance), as well as environmental factors and comorbidities, may contribute to varying disease courses within families.

Clinical observation of 10 patients from 4 unrelated families with ADPKD. In each family, genetic testing was performed on the probands, confirming a PKD1 gene mutation. To compare disease progression, the mean annual change in height-adjusted total kidney volume (htTKV) over the observation period was compared. The median observation period was 4 [2; 4.5] years. Categorical variables were compared using Fisher's exact test. A p-value < 0.05 was considered statistically significant.

From 2020 to 2025, in the nephrology department of the National Medical Research Center for Pediatrics and Pediatric Surgery named after Yu.E. Veltischev, 4 families were observed in which ADPKD was diagnosed in siblings (n = 10). Arterial hypertension was detected in 6 out of 10 patients (60%). No other comorbidities were identified. In Family 1, a homozygous variant leading to the amino acid substitution p.Ile3167Phe was identified. The mean annual increase in htTKV in the male sibling was 6.5 ml/min/year, and in the female sibling – 2.25 ml/min/year. In Family 2, a nucleotide sequence variant in exon 43 of the PKD1 gene in heterozygous state, leading to termination of protein synthesis at position 3978, was identified. The mean annual increase in htTKV in the male sibling was 52 ml/min/year, in the older sister – 14.8 ml/min/year, and in the younger sister – 4 ml/min/year. In Family 3, two heterozygous mutations in the PKD1 gene were identified: p.Thr2720HisfsTer102, leading to the formation of a stop codon, and a missense mutation p.Pro820Ala. In contrast, the male siblings showed a smoother course: the mean annual increase in htTKV in the older male sibling was 11 ml/min/year, in the younger male sibling – 6 ml/min/year, and in the female sibling – 15 ml/min/year. In Family 4, a nucleotide sequence variant in exon 15 of the PKD1 gene, leading to the formation of a stop codon p.Tyr1599Ter, in heterozygous state was identified. The mean annual increase in htTKV in the male sibling was 92 ml/min/year, and in the female sibling – 2.3 ml/min/year. Thus, in 1 out of 4 families (25%), high discordance in the clinical course of ADPKD was observed, defined as a significant deviation of the individual mean annual change in htTKV from the family average, and it was associated with the p.Tyr1599Ter PKD1 gene variant. No sex differences were found in the prevalence of disease course discordance among families (p > 0.05).

The cause of intrafamilial phenotypic variability may lie in the possible influence of modifier genes, epigenetic factors, as well as polygenic factors and environmental influences. This complicates the diagnosis and prognosis of the disease and necessitates a personalized approach to each child, even when working with siblings within the same family.