Detection of Alport gene variants in children and young people with persistent haematuria

Abstract

Background: Genetic kidney disease is an important cause of persistent microscopic haematuria in children and young people. We aimed to determine the frequency of variants in the Alport syndrome genes (COL4A3, COL4A4 or COL4A5) in individuals under 18 years of age presenting with persistent microscopic haematuria to a single specialist centre in the UK over a 10-year period.

Methods: We conducted a retrospective longitudinal study of individuals referred to a tertiary paediatric nephrology service with persistent microscopic haematuria between April 2012 to 2022.

Results: A total of 224 individuals (female 51.8%) were evaluated with persistent microscopic haematuria of greater than 6 months duration. The age at presentation was 7.5 ± 4.3 years (mean ± SD) with a duration of follow-up of 6.8 ± 4.6 years (mean ± SD). Targeted exome sequencing was performed in 134 individuals and 91 (68%) had a pathogenic or likely pathogenic variant in COL4A3, COL4A4 or COL4A5. Only 49.5% of individuals with identified variants had a family history of microscopic haematuria documented and 37.4% (34/91) had additional proteinuria at presentation. COL4A5 was the most common gene affected and missense variants affecting glycine residues were the most common variant type.

Conclusion: Over two-thirds of children and young people who underwent genetic testing had an identifiable genetic basis for their microscopic haematuria and over half did not have a documented family history. Genetic testing should be part of the evaluation of persistent microscopic haematuria despite a negative family history.

Keywords: Genetic kidney disease; Genetic testing; Microscopic haematuria.

A higher resolution version of the Graphical abstract is available as Supplementary information

Fig. 1

Outcomes of genetic testing for microscopic haematuria. A total of 224 children and young people aged ≤ 18 years with persistent MH were referred over the 10-year period. Targeted exome sequencing was performed in 134 individuals. A positive genetic test was observed in 91/134 individuals (68%) who were identified to have a pathogenic or likely pathogenic variant in COL4A3, A4, or A5. Of the 90 individuals who did not undergo genetic testing, 19 individuals were assumed obligate carriers from affected relatives

Fig. 2

a Molecular diagnosis of the whole cohort. A pathogenic or likely pathogenic variant in COL4A5 was most common, with 42 individuals identified (26 hemizygous males and 16 heterozygous females). Pathogenic or likely pathogenic variants in COL4A3 were identified in 16 individuals (10 heterozygous, 5 compound heterozygous and 1 homozygous) and pathogenic or likely pathogenic variants in COL4A4 were identified in 32 individuals (27 heterozygous, 1 compound heterozygous and 4 homozygous). The genetic variant for one individual with autosomal recessive AS was not available in their health records. b Variant characteristic for whole cohort. 90 pathogenic or likely pathogenic variants in COL4A3, A4 or A5 were identified with missense variants affecting glycine residues being most frequently identified in 40 individuals, followed by nonsense variants in 25 individuals, splicing variants in 11 individuals and missense variants affecting non-glycine residues in 6 individuals. Frameshift and in-frame deletion variants were the least commonly observed within our cohort with 4 individuals identified to have each of these variant types

Fig. 3

a Frequency of clinical features in children with COL4A5 variants, by sex. Family history of MH (87.5%), use of ACE-I/ ARB (73.1%), hearing loss (72.7%) and proteinuria (57.7%) were amongst clinical features most observed in males. In comparison, a lower frequency of family history of microscopic haematuria (50%), use of ACE-I/ ARB (50%), proteinuria (37.5%) and hearing loss (10%) were observed in females. Ocular involvement (22.2%) and chronic kidney disease (7.7%) were features only observed in males with COL4A5 variants in our cohort. b Distribution of frequency of clinical features in children with heterozygous COL4A3/A4 variants compared to children with autosomal recessive AS. The frequencies of family history of MH (75%), proteinuria (66.7%), hearing loss (50%), chronic kidney disease (41.7%) and use of ACE-I/ ARB (33.3%) were higher in individuals with autosomal recessive AS compared to individuals with heterozygous COL4A3/A4 variants. Ocular involvement was observed in one individual (7.7%) with heterozygous COL4A3/A4 variant and none of the individuals with autosomal recessive AS. Chronic kidney disease was observed in none of the individuals with heterozygous COL4A3/A4 variants in our cohort