Segregation of hematuria in thin basement membrane disease with haplotypes at the loci for Alport syndrome

Background. Inherited hematuria is common and is usually attributed to thin basement membrane disease (TBMD). The aim of this study was to determine how often hematuria in families with TBMD segregated with haplotypes at the chromosomal loci for autosomal excessive and X-linked Alport syn drome (CQL4A3/COL4A4 and COL4A5, respectively). Methods. The families of 22 individuals with TBMD on renal biopsy and with urinary glomerular red blood cell (RBC) counts of more than 501000/mL were studied using phase-contrast microscopy of the urine and DNA microsatellite markers. Eighteen families had at least two members with hematuria. Results. Hematuria segregated with or was consistent with segregation at the COL4123/COL4A4 locus, in eight (36%) families (P < 0.05 in 5 of these) and at the COL4A5 locus in four (18%) families (P < 0.05 in 2). The lack of segregation in the other 10 (45%) families may have occurred because of incomplete penetrance of the hematuria, de novo mutations, coincidental hematuria in other family members, or the presence of a novel gene locus. In four different families, three of which had hematuria that segregated with the COL4A3/COL4A4 locus, four family members with the hematuria haplo-type had spouses with coincidental hematuria (4 of 29, 14%). However, none of their four offspring who had also inherited the hematuria haplotype had the clinical features of autosomal recessive Alport syndrome. Conclusions. Hematuria in families with TBMD commonly segregates with the COL343/COL4A4 locus and thus results from mutations in the same genes as autosomal recessive Alport syndrome. Sometimes TBMD may be confused with the carrier state for X-linked Alport syndrome. However, nearly half of the families in this study had hematuria that did nut segregate with the loci for either autosomal recessive or X-linked Alport syndrome.