Familial Idiopathic Glomerular Disease due to a Unique Renal-Predominant Phenotype of MYH9-Related Disease: A Case Report.

Introduction: MYH9-related disease (MYH9-RD) is a rare genetic cause of proteinuric kidney disease. It typically manifests as a syndromic condition, presenting with macrocytic thrombocytopenia, sensorineural hearing loss (SNHL), chronic glomerulopathy, elevated liver enzymes, and early-onset bilateral cataracts. In accordance with CARE guidelines, we present a case report of a father and daughter with renal-predominant MYH9-RD due to a recently described missense variant affecting the head domain of non-muscle myosin heavy chain IIA.

Case presentations: Patient 1 was an 18-year-old woman with childhood proteinuria who presented with severely advanced kidney failure. Dialysis was initiated as a bridge to a living unrelated renal transplant (LURT). Family history was notable for proteinuric kidney disease in her father (patient 2). Eight years later, genetic testing identified a likely pathogenic missense variant in the head domain of the MYH9 gene (c.1271G>A, p.R424Q). A predictive structural model was obtained via AlphaFold Protein Structure Database, in which the mutation interrupts hydrogen bonding and π-cation interactions, likely leading to protein misfolding. Subsequent clinical screening revealed persistent mild thrombocytopenia and elevated liver enzymes, without cataracts or SNHL. Patient 2 was a 53-year-old man with childhood proteinuria who eventually presented with stage 4 chronic kidney disease and soon after underwent LURT. After patient 1's genetic diagnosis, he was confirmed to have the same mutation by genetic testing. Subsequent screening revealed mild thrombocytopenia and elevated liver enzymes with hepatic steatosis progressing to cirrhosis, without cataracts or SNHL.

Conclusion: The finding of this MYH9 p.R424Q variant confirmed a diagnosis of MYH9-RD in these patients. MYH9 variants affecting the head domain typically result in severe thrombocytopenia. This recently reported head domain variant caused severe renal manifestations with mild thrombocytopenia and no manifestations of SNHL or cataracts in both patients, suggesting that this variant causes a renal-predominant form of MYH9-RD.