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Alport syndrome is a hereditary glomerular disorder caused by pathogenic variants in COL4A3, COL4A4, or COL4A5, encoding type IV collagen α-chains. It is characterized by hematuria, progressive renal dysfunction, sensorineural hearing loss, and ocular abnormalities. Genetic testing is essential for confirming the diagnosis, progression, and donor selection. However, targeted exome sequencing often fails to detect certain variant types, especially deep intronic variants and large deletions. We evaluated the clinical utility of whole-genome sequencing (WGS) in three pediatric patients with clinically suspected Alport syndrome who remained genetically undiagnosed after targeted exome sequencing.
Three pediatric patients underwent targeted exome sequencing covering COL4A3, COL4A4, COL4A5, and approximately 140 additional kidney disease-related genes. Copy number variation (CNV) analysis and multiplex ligation-dependent probe amplification (MLPA) were performed where indicated. In all cases, targeted exome sequencing did not identify any pathogenic variants explaining the phenotype, and WGS was conducted. Deep intronic variants identified by WGS were evaluated in silico using SpliceAI, and those predicted pathogenic were further assessed with minigene assays.
Patient 1: A 16-year-old girl who presented with recurrent gross hematuria from infancy. A kidney biopsy performed at age two showed lamellation of the glomerular basement membrane (GBM) and a mosaic pattern of α5 collagen staining. WGS revealed a deep intronic COL4A5 (NM_000495.5) variant (c.276+1306G>A), predicted pathogenic by SpliceAI and confirmed by minigene assay, establishing X-linked Alport syndrome (XLAS).
Patient 2: A 3-year-old girl who also had recurrent gross hematuria from infancy, along with persistent proteinuria and normal kidney function. Her kidney biopsy revealed an α5 mosaic pattern similar to that observed in Patient 1. WGS identified a deep intronic COL4A5 variants (c.3791-1066A>G). Minigene assays confirmed aberrant splicing through the inclusion of cryptic exons, supporting their pathogenicity.
Patient 3: A 6-year-old girl with gross hematuria beginning at age four and proteinuria. Biopsy revealed a basket-weave appearance of the GBM. Immunostaining showed absence of α5 collagen in the GBM and preserved staining in Bowman’s capsule, suggestive of autosomal recessive Alport syndrome (ARAS). CNV analysis and MLPA had identified a heterozygous COL4A3 exon 18–19 deletion inherited from her father, but no maternal variant was detected. WGS revealed a large heterozygous deletion spanning COL4A3 and COL4A4, establishing compound heterozygosity consistent with ARAS and indicating additional digenic Alport syndrome due to involvement of both CO4A3 and COL4A4.
All identified variants demonstrated strong genotype–phenotype correlation and were consistent with each patient’s clinical course and family history.
These cases demonstrate the diagnostic value of WGS in detecting pathogenic variants undetectable by targeted exome sequencing in Alport syndrome. Incorporating WGS and functional validation can enhance diagnostic precision and inform patient and family management, especially when clinical or histological findings strongly suggest Alport syndrome but targeted exome sequencing is inconclusive.
