CLINICAL VARIABILITY OF ALPORT SYNDROME IN CHILDREN WITH MISSENSE COL4A5 VARIANTS

Abstract Background and Aims The phenotype-genotype relation is well established in patients (especially male) with X-linked Alport syndrome (XLAS). The aim of study was to define the spectrum of COL4A5 pathogenic variants and impact of missense mutation on disease progression. Method The NGS-based genetic testing of COL4A3, COL4A4, COL4A5 was performed in 186 children with suspected Alport syndrome. The comparison of clinical symptoms (frequency, age of presentation of macrohematuria, proteinuria, eGFR decrease, sensorineural deafness (SND), level of proteinuria (mg/m2/day) and eGFR (ml/min/1.73m2) at the last presentation) was carried out in male with XLAS due to different COL4A5 variants. Results The XLAS was diagnosed in 93 children (Ме 7,5[4;11], 51М) from 79 families. The following COL4A5 variants were revealed: missense (n=70, q=0.75), splice site (n=10 from 9 families, q=0.11), frame shift (n=6, q=0.06), nonsense (n=7, q=0.08). Missense variants were presented by COL4A5 c.1871G>A, p.(Gly624Asp) in 26% of cases (n=18). The mean age of ESRD was lower in male family member (35[24;35] years vs 48[40;55], p=0.023) with non COL4A5 p.(Gly624Asp). There was no difference in age on last presentation (13[9;14] vs 12[8;15], p=0.091) between pts with COL4A5 p.(Gly624Asp) and other missense variants. There was significant difference between the male with p.Gly624Asp and other missense variants in frequency of proteinuria (0.61 vs 0.25, p=0.043), SND (0.5 vs 0.08, p=0.03), age at onset (5[3;7] vs 14[8;16], p=0.02) and degree of proteinuria (441[78;1158] vs 66[22;160], p=0.023) and eGFR level (83[66;109] vs 96[91;104], p=0.048) at the last examination. Conclusion The XLAS is caused by missense variants in ¾ of cases in our cohort. We confirmed the other European studies results: the COL4A5 p.(Gly624Asp) is the most common variant of missense mutations characterized by mild phenotype of XLAS.