Genetic diagnosis of hereditary kidney disease in pediatric patients through whole-exome sequencing and mitochondrial DNA analysis

Background: Identifying the genetic cause of hereditary kidney disease is essential for appropriate management. However, pediatric patients often present with nonspecific renal symptoms such as proteinuria, hematuria, or both, making accurate diagnosis difficult. Mitochondrial diseases are also an important but underrecognized etiology of hereditary kidney disorders. This study aimed to assess the diagnostic utility of whole-exome sequencing (WES) combined with mitochondrial DNA (mtDNA) analysis and to describe the clinical and genetic features of pediatric patients presenting with isolated proteinuria, combined hematuria and proteinuria, or hematuria with a relevant family history. Methods: DNA was extracted from peripheral blood leukocytes of 77 pediatric patients with hematuria and/or proteinuria with or without family history. WES and mtDNA analyses were conducted to identify underlying genetic etiologies. Results: The overall molecular diagnostic yield was 54.5% (42/77) with COL4A-related nephropathy (29 cases) being the most prevalent diagnosis. Notably, one patient with no systemic symptoms except for renal manifestations was identified with the m.3243A>G variant in MT-TL1, which is associated with the MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndrome. This patient's initial and predominant presentation was gross and microscopic hematuria, diverging from typical MELAS-associated kidney disease. Conclusion: WES proved valuable in diagnosing hereditary kidney diseases in pediatric patients with nonspecific urinalysis findings. Incorporating mtDNA analysis further improved diagnostic yield and enabled identification of atypical presentations of mitochondrial disorders, such as MELAS, even when renal symptoms were isolated.