Background: Alport syndrome (AS) is an inherited familial nephropathy,
characterized by progressive hematuric nephritis, bilateral sensorineural hypoacusis and
ocular abnormalities. X-linked AS (XLAS) is the major AS form and is clinically
heterogeneous, and it is associated with defects in the collagen type IV alpha 5 chain
Objective: The purpose of this research is to detect the genetic defect responsible for
renal disorder in a 3-generation Han-Chinese pedigree.
Methods: Detailed family history and clinical data of the family members were collected
and recorded. Whole exome sequencing (WES) was applied in the proband to screen
potential genetic variants, and then Sanger sequencing was used to verify the variant
within the family. Two hundred unrelated ethnically matched normal individuals
(male/female: 100/100, age 37.5 ± 5.5 years) without renal disorder were recruited as
Results: Three patients (I:1, II:1 and II:2) presented microscopic hematuria and
proteinuria, and the patient I:1 developed uremia and end stage renal disease (ESRD)
by age 55 and showed sensorineural hearing loss. Patient II:2 developed mild left ear
hearing loss. Cataracts were present in patients I:1 and II:1. A COL4A5 gene missense
variant, c.2156G>A (p.G719E), located in the Gly-X-Y repeats of exon 28, was identified
to co-segregate with the renal disorder in this family. The variant was absent in 200
ethnically matched controls.
Conclusion: By conducting WES and Sanger sequencing, a COL4A5 missense variant,
c.2156G>A (p.G719E), was identified to co-segregate with the renal disorder, and it is
possible that this variant is the genetic cause of the disorder in this family. Our study
may extend the mutation spectrum of XLAS and may be useful for genetic counseling of
this family. Further functional studies associated with genetic deficiency are warranted in
the following research.