Kidney Disease Associated With Mono-allelic and Variants: A Case Series of 17 Families.

RATIONALE & OBJECTIVE: Mono-allelic variants in and () have been identified in a spectrum of glomerular basement membrane nephropathies, including thin basement membrane nephropathy and autosomal dominant Alport syndrome. With the increasing use of next generation sequencing, mono-allelic variants are detected more frequently, but phenotypic heterogeneity impedes counseling. We aimed to investigate the phenotypic spectrum, kidney biopsy results, and segregation patterns of patients with mono-allelic / variants identified by whole exome sequencing.

STUDY DESIGN

Case series.

SETTING & PARTICIPANTS: We evaluated clinical and pathologic characteristics of 17 Dutch index patients with mono-allelic variants in / detected by diagnostic whole exome sequencing and 25 affected family members with variants confirmed by Sanger sequencing.

RESULTS

Eight different mono-allelic variants were identified across members of 11 families, comprising 7 glycine substituted missense variants and 1 frameshift variant. All index patients had microscopic hematuria at clinical presentation (median age 43 years) and 14 had (micro)albuminuria/proteinuria. All family members showed co-segregation of the variant with at least hematuria. At end of follow-up of all 42 individuals (median age 54 years), 16/42 patients had kidney function impairment, of whom 6 had kidney failure. Reports of kidney biopsies of 14 patients described thin basement membrane nephropathy, focal segmental glomerulosclerosis, minimal change lesions, and Alport syndrome. Electron microscopy images of 7 patients showed a significantly thinner glomerular basement membrane compared with images of patients with idiopathic focal segmental glomerulosclerosis and other hereditary glomerular diseases. No genotype-phenotype correlations could be established.

LIMITATIONS

Retrospective design, ascertainment bias toward severe kidney phenotypes, and familial hematuria.

CONCLUSIONS

This study confirms the wide phenotypic spectrum associated with mono-allelic variants, extending from isolated microscopic hematuria to kidney failure with high intra- and interfamilial variability.