UNCOMMON NOVEL GENETIC MUTATIONS IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE: IMPLICATIONS FOR EARLY ONSET AND SEVERE PHENOTYPES

Introduction:

About 90% of autosomal dominant polycystic kidney disease (ADPKD) patients have pathogenic variants in the primary genes PKD1 and PKD2, around 10% lack detectable variants in these genes, indicating genetic heterogeneity. Recently, pathogenic variants in the GANAB gene and the discovery of gene modifiers of ADPKD have been identified, suggesting that these variants may contribute to more severe phenotypes.

Methods:

This retrospective descriptive study presents a case report involving three individuals from the same family diagnosed with ADPKD, who exhibit uncommon genetic mutations. The study includes a comprehensive review of patient case files, with details compiled, analyzed, and presented as a case report.

Results:

Case-1 A 35-year-old female from a non-consanguineous marriage presented with palpitations and recurrent, self-resolving, hematuria over the past six months. Her elder brother (Case 2) has had cystic kidney disease since age 15 and now has chronic kidney disease stage IV. Her father, one uncle, two aunts, and one cousin also had cystic kidney disease. Her father, uncle, and aunts died at age 45 from CKD stage V and cousin progressed to ESRD and underwent a kidney transplantation at age 42, and is currently well. Her 9-year-old son (Case 3) also has polycystic kidney disease. [Figure 1]

Blood pressure was 116/70 mmHg. Her renal function was normal. Urine microscopy showed 5-6 RBCs per high-power field. Ultrasonography revealed multiple cysts in both the cortex and medulla of kidney. MRI showed bilateral enlarged kidneys (Right: 13 x 7.3 x 6.0 cm, volume 284 ml; Left: 13 x 7 x 6.8 cm, volume 323 ml) with multiple hyperintense lesions on T2-weighted imaging. [Figure 2]

Case -2: A 39-year-old male with a history of hypertension since age 13 and polycystic kidney disease (PKD) since age 15 presented with painful hematuria and pedal edema for the past 20 days. The hematuria resolved after 3 days. He has a 15-year-old son and a 12-year-old daughter, both with polycystic kidney disease, and previously lost three children due to premature birth. He is currently taking Telmisartan 40 mg and Amlodipine 5 mg daily. Examination revealed pallor and pedal edema. Laboratory tests showed hemoglobin (8.5 gm/dL), serum creatinine (2.69 mg/dL), blood urea nitrogen (65 mg/dL), parathyroid hormone (164 pg/mL), and 25-OH vitamin D (15.6 ng/mL). Urine microscopy showed 15-20 RBCs per high-power field. Ultrasonography revealed bilateral multiple cysts in both the cortex and medulla of kidney.

Case 3: A 9-year-old asymptomatic male underwent screening for polycystic kidney disease. Blood pressure was 100/70 mmHg. His developmental milestones, renal function and urine analysis were normal. Ultrasonography showed bilateral multiple cysts of varying sizes (7-8 on the right and 4-5 on the left) in both the cortex and medulla of kidney.

Mutation Analysis:

Next-generation whole exome sequencing identified an autosomal dominant heterozygous mutation of uncertain significance (chr16: g.2090860_2090879del; c.12003+14_12003+33del) in intron 43 of the PKD1 gene at the 5' splice site, as well as a heterozygous missense mutation (c.4970C>G; p.Ala1657Gly) in exon 48 of the COL4A4 gene in the index case. Targeted Sanger sequencing of the other two cases confirmed the presence of the same mutation in intron 43 of the PKD1 gene.

Conclusions:

This case report describes a novel, uncommon mutation in the PKD1 gene in the index case and their family members affected by ADPKD. Although this mutation is currently classified as a variant of uncertain significance, it appears to have resulted in an early onset and severe disease phenotype within this particular pedigree.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.