731 Identifying phenotypic features to inform genetic screening in children with persistent haematuria

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Aims Persistent incidentally detected haematuria is prevalent in paediatrics and is commonly referred to paediatric nephrologists. It is important to identify which children are at higher probability of having an underlying genetic diagnosis. Mutations in COL4A3, COL4A4 and COL4A5 that make up the glomerular basement membrane results in a clinical spectrum of disease including Alport syndrome and thin basement membrane disease with widely differing prognoses. Progression to chronic kidney disease can occur during childhood making early interventions important. The benefits of genetic diagnosis are many, including determining carrier status, understanding disease phenotype and prognosis, early implementation of ACEI therapy as well as avoiding invasive renal biopsies. However, genetic testing is costly and so the aim of this project is to identify features that make testing more likely to be positive. Methods We analysed a group of children referred to our tertiary paediatric nephrology unit, for persistent microscopic haematuria between 2014-2018 and who had had genetic panels assessing for variants in COL4A3,4,5 and 6 and NPHS2 by next generation sequencing. The purpose of this retrospective cohort review was to assess the clinical features of those tested, and to investigate if any of those features corresponded with a greater likelihood of predicting a genetic diagnosis. Information was obtained by accessing electronic clinical records. Of the 99 children who had genetic testing, 5 children were excluded due to insufficient available information. The characteristics that were assessed in the 94 remaining children included: hearing loss or visual problems either in the proband or in first degree relatives, proteinuria at the time of referral, family history of renal disease, abnormal renal function, hypertension and proteinuria, and a history of previous urinary tract infections. The probability of certain characteristics being associated with an underlying genetic diagnosis was evaluated by calculating likelihood ratios Results Of the 94 children, 65% were male. Median age was 9 years (range 9 months-16 years). Median time from haematuria onset to referral to the tertiary nephrology centre was 7 months (range 1-108 months) and median time from referral to genetic testing was 8 months (range 1-86 months). 28% of the children were found to have an underlying genetic cause of their haematuria or had genetic variants of yet unknown clinical significance (VUS). In the children who had VUS, 38% of mutations were in COL4A3, 31% in COL4A4, 15% in COL4A5, 8% in COL4A6 and 8% in NPHS2. Of the characteristics analysed, co-existing visual problems demonstrated a notable increased likelihood of a genetic diagnosis (likelihood ratio=25). Co-existing family history of renal disease only led to a marginal increased likelihood of a genetic diagnosis (likelihood ratio=1.87). Conclusion This is the largest single centre review to date correlating clinical phenotype in children with persistent haematuria with COL4 genetic testing. From this we can infer that children who present with haematuria should have an early ophthalmological assessment and those who also have visual impairment should be prioritised for genetic testing to assess for variations in the COL4A genes as this increases the pre-test probability of a positive genetic result.

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