A Novel COL4A5 Pathogenic Variant Joins the Dots in a Family with a Synchronous Diagnosis of Alport Syndrome and Polycystic Kidney Disease

Abstract

Alport Syndrome (AS) is the most common genetic glomerular disease, and it is caused by COL4A3, COL4A4, and COL4A5 pathogenic variants. The classic phenotypic spectrum associated with AS ranges from isolated hematuria to chronic kidney disease (CKD) with extrarenal abnormalities. Atypical presentation of the disorder is possible, and it can mislead the diagnosis. Polycystic kidney disease (PKD), which is most frequently associated with Autosomal Dominant PKD (ADPKD) due to PKD1 and PKD2 heterozygous variants, is emerging as a possible clinical manifestation in COL4A3-A5 patients. We describe a COL4A5 novel familial frameshift variant (NM_000495.5: c.1095dup p.(Leu366ValfsTer45)), which was associated with AS and PKD in the hemizygous proband, as well as with PKD, IgA glomerulonephritis and focal segmental glomerulosclerosis (FSGS) in the heterozygous mother. Establishing the diagnosis of AS can sometimes be difficult, especially in the context of misleading family history and atypical phenotypic features. This case study supports the emerging genotypic and phenotypic heterogeneity in COL4A3-A5-associated disorders, as well as the recently described association between PKD and collagen type IV (Col4) defects. We highlight the importance of the accurate phenotyping of all family members and the relevance of next-generation sequencing in the differential diagnosis of hereditary kidney disease.

Keywords: Alport Syndrome; COL4A5; phenotypic variability; polycystic kidney disease; sensorineural hearing loss.

Figure 1

Clinical characterization of the three-generation pedigree of the family. Gray-filled individuals manifested polycystic kidney disease (PKD). Blue-filled individuals manifested either microscopic or macroscopic persistent hematuria. Yellow-filled individuals manifested sensorineural hearing loss (SNHL). Red-filled individuals manifested proteinuria. The proband (III-1) and his mother (II-2) were screened for the NM_000495.5: c.1095dup p.(Leu366ValfsTer45) variant in the COL4A5 gene (red arrow).

Figure 2

Renal ultrasound (US) of the proband (a–c) showing bilateral mildly enlarged kidneys (13 cm on the left, 12 cm on the right) and several small-to-large cysts, with the largest on the left measuring 6.8 × 6.2 cm. Renal US of the mother (d–f) showing kidneys of normal volume (10.7 cm on the left, 10.5 cm on the right) and multiple bilateral cysts of varying sizes, with the largest on the right measuring 1.8 × 1.2 cm. R, right; L, left.