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Genetic analysis in patients with alport syndrome and thin glomerular basement membrane disease in croatia - with case example

INTRODUCTION AND AIMS: We present the project of genetical analysis of the patients with Alport's syndrome (AS) and Thin glomerular basement membrane disease (TGBMD). Croatian science foundation funded project , Genotype - phenotype correlation in Alport's syndrome and thin glomerular basement membrane disease is an attempt to contribute to better understanding of these diseases. METHODS: We analysed data from our hospital's kidney biopsy registry. We are also presenting, two female patients (mother and daughter) aged 48 and 23 presented with asymptomatic proteinuria and erythrocyturia. Ultrasound guided kidney biopsy was performed using 16 Gauge needle. Light, immunofluorescent and electron microscopy analysis was performed. Male patient, age 21, (son), presented with progressive chronic kidney disease and recieved kidney transplant. Clinical geneticist analysed family data. Blood samples were obtained from both females while male declined to participate in the study. DNA was isolated and next genome sequencing performed testing for mutations in collagen type 4 (COL4) chaines. RESULTS: Out of 1900 kidney biopsies in our hospital's registry we noticed 7% of prevalence of AS and TGBMD. Patients clinicaly presented with erythrocyturia and daily proteinuria between 0.5-1 grams and varying levels of eGFR. We present an example of family with AS. Older female has chronic kidney disease with eGFR (CKD-EPI formula) 40 ml/min/1.73m2 and younger female has normal eGFR with asymptomatic proteinuria and erythrocyturia. Pathohistologic analysis of kidney samples of two female patients revealed signs of AS on electron microscopy, while light microscopy revealed only secondary focal segmental glomerulosclerosis (FSGS). Immunohistochemical analysis showed α3 and α5 COL4 chaines glomerular staining pattern characteristic for X linked AS. Genome analysis found COL4 α5 stop codone mutation, c.2950C>T ; p.Gln984Ter on X chromosome. This is a known mutation in AS which in males phenotypically presents as more rapid progressive loss of kidney function while slower disease progression is usually present in females. CONCLUSIONS: AS causes chronic kidney disease but recently published data showed TGMD can lead to FSGS and end-stage renal disease (ESRD), usually in later age than in AS. , Genotype-phenotype correlation in Alport's syndrome and thin glomerular membrane disease“ funded by Croatian science foundation will include 400 patients with AS and TGMD and family members with possible expansion of project and inclusion of patients from other neighbouring countries. Project will determine prevalence and types of various COL4α chains mutations in Croatian patients with AS. Basic urin analysis in family members of patients with AS could lead to earlier diagnosis of kidney disease. This will improve risk stratification in individual family members and allow better health care quality.

hereditary nephritis ; Croatia ; thin basement membrane ; disease ; genetic analysis

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