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

MYH9-related disease (MYH9-RD) is a rare but underrecognized genetic cause of chronic glomerulopathy. Heterozygous pathogenic variants in MYH9, which encodes for a subunit of the non-muscle myosin heavy chain IIA (NMMIIA), leads to a constellation of manifestations including macrocytic thrombocytopenia, elevated liver enzymes, early-onset bilateral cataracts, sensorineural hearing loss (SNHL), and proteinuric glomerular disease [1]. Due to its characteristic kidney pathologic findings of focal segmental glomerulosclerosis (FSGS), foot process effacement, and thin glomerular basement membranes in conjunction with bilateral SNHL, it is often mistaken for a type IV collagenopathy [2]. The hematologic sequelae are often the most prominent and severe features of this disease, with nephropathy only occurring in 30% of patients and with varying degrees of severity [3, 4]. Here, in accordance with CARE guidelines, we report a case of a father and daughter who presented with a recently described MYH9 variant, manifesting as renal-predominant MYH9-RD. The CARE Checklist was completed by the authors for this case report and is available as online supplementary material.

Patient 1 was an 18-year-old woman of Ashkenazi Jewish descent with a history of menorrhagia, who initially presented with acute shortness of breath, hypertension, ecchymoses, and anemia. Diagnostic evaluation revealed hemoglobin of 4.7 g/dL, serum creatinine of 27.1 mg/dL, and bilateral shrunken kidneys (left 5.2 cm and right 5.6 cm) on ultrasound. Serologies for antineutrophil cytoplasmic antibody, antinuclear antibody, and anti-glomerular basement membrane antibodies were negative. She was started on hemodialysis and referred for transplant evaluation. At the time of transplant evaluation, her laboratory values are as noted in Table 1. She received a living unrelated renal transplant (LURT) 4 months after starting dialysis. The patient reported that a urinalysis performed at age 5 had demonstrated 2+ protein and 2–4 red blood cells per high-powered field, which was not further investigated. Family history was notable for childhood proteinuria and progressive chronic kidney disease in her father (see patient 2 below). No other family members had any kidney or urinary abnormalities.

Patient 1’s father presented in the same year with progressive proteinuric kidney disease. Patient 2 was a 53-year-old man of Ashkenazi Jewish descent with a history of type 2 diabetes, hypertension, and hyperlipidemia. He had proteinuria since age 2, for which a biopsy performed at age 17 was reportedly inconclusive, and he was managed with salt restriction. He experienced slowly progressive loss of kidney function with serum creatinine rising to 2.5 mg/dL prior to the onset of type 2 diabetes at age 45. At the time of presentation, his laboratory values are as noted in Table 1, consistent with stage 4 chronic kidney disease. He underwent preemptive LURT at age 54.

Seven years after her LURT, patient 1 underwent research-level genetic testing via whole exome sequencing [5]. We identified a heterozygous variant (c.1271G>A, p.R424Q) in MYH9 (NM_002473.5), which was confirmed clinically in a CLIA-certified laboratory and returned to the patient. Subsequent genetic testing in patient 2 confirmed that he also harbored the same MYH9 genetic variant.

The p.R424Q missense variant is absent in control populations (gnomAD database), suggesting that it is not a benign variation. In silico tools predict that this variant is damaging (REVEL score of 0.801). This variant has been reported in the literature in multiple individuals with features of MYH9-RD [2, 6]. The p.R424Q variant is located in the head domain of MYH9, though other pathogenic missense variants in this domain typically result in more severe hematological manifestations [3, 7]. Based on the allelic, computational, and population data cited above, this variant was classified using the American College of Medical Genetics and Genomics (ACMG) criteria as likely pathogenic, and this genetic finding resulted in a molecular diagnosis of MYH9-RD [8].

In addition to this variant classification data, a predicted structure of MYH9 was obtained from the AlphaFold Protein Structure Database (AF-P35579-F1-model_v4) to help clarify the variant’s effect on protein structure (Fig. 1). The wild-type and variant proteins were modeled in ChimeraX to depict the structural context of R424 and illustrate the likely consequences of p.R424Q on the local protein structure [9]. Structural analysis of MYH9 p.R424Q suggests possible mechanisms for its likely pathogenicity. Although no protein coordinates based on experimental data have been published on the region of MYH9 containing R424, numerous structures have been published for homologous myosin domains, and the AlphaFold Protein Structure Database contains a high confidence structural prediction for the region. Based on the AlphaFold prediction, the side chain of R424 engages with a neighboring alpha helix by hydrogen bonding with main chain carbonyls and participating in a π-cation interaction with a tryptophan (shown in Fig. 1). Mutation of the large, positively charged arginine residue to the smaller, uncharged glutamine in MYH9 p.R242Q will both attenuate the intramolecular hydrogen bonding between the helices and ablate the π-cation interaction. The loss of these interactions may disturb the packing of the alpha helices, likely leading to misfolding and loss of function.

Since her transplant, patient 1 (now 32 years old) had stable allograft function without proteinuria or hematuria. Ongoing laboratory abnormalities included mild thrombocytopenia (platelets 100–150 × 10³/μL), and mild elevation in transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 40–100 U/L). After her diagnosis of MYH9-RD, she underwent hematologic evaluation, which was notable for elevated mean platelet volume (12–14.5 fL) and immature platelet fraction (8.4–12.0%). A blood smear showed giant platelets and a few neutrophils with Döhle bodies (image was not available). Otologic evaluation did not reveal SNHL, nor did ophthalmologic evaluation reveal any signs of early cataracts.

Patient 2 had a more complicated clinical course, although delayed as compared to his daughter. His allograft function remained stable without proteinuria or hematuria. Like his daughter, he continued to have mild thrombocytopenia (platelets 80–200 × 10³/μL), with elevated mean platelet volume (11.0–13.5 fL) and immature platelet fraction (9.5–11.8%). A blood smear was not available. He did not develop any otologic or ophthalmologic abnormalities. For 12 years, he had stable elevations of transaminases (AST and ALT 30–140 U/L) without clinical manifestations of liver dysfunction. However, he subsequently developed abrupt-onset ascites and altered mental status, leading to a diagnosis of cirrhosis and hepatic encephalopathy. Serologic workup and ascitic fluid analysis were unrevealing. Trans-jugular liver biopsy revealed a cirrhotic appearing liver without steatosis nor any specific etiological findings. He was listed for liver transplantation but ultimately died of complications of liver failure at age 66; as a postmortem was not performed, the presumptive etiology of his cirrhosis was metabolic-associated fatty liver disease.

MYH9-RD has previously been characterized under different names based on the presence of specific clinical features, including Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, Sebastian platelet syndrome, and Alport syndrome with macrothrombocytopenia. The prevalence of MYH9-RD is not well established but is estimated as high as 1 in 20,000, with nephropathy reported in approximately 30% of cases [10]. MYH9 encodes for the myosin-9 protein, which is a subunit of the NMMIIA. NMMIIA interacts with actin and plays a role in cell motility, maintenance of cell shape, and cytokinesis. While the pathogenesis of MYH9-RD is poorly understood, it is believed that pathogenic variants cause disease via a dominant-negative effect [11]. It is hypothesized that, since NMMIIA is involved in maintaining and disassembling adhesion complexes, mutations would result in impaired slit diaphragm structure and function, leading to proteinuria and glomerulosclerosis [12]. The predisposition to protein misfolding suggested by the structure predicted by the AlphaFold2 model may provide an explanation for how this mutation leads to slit diaphragm impairment.

The condition is characterized by a spectrum of clinical features including thrombocytopenia, hearing loss, cataracts, elevated liver enzymes and glomerulopathy. Most predominant are the hematological features of macrothrombocytopenia and aggregates of the MYH9 protein in the cytoplasm of neutrophil granulocytes, called Döhle bodies. It is common for individuals with MYH9-RD to show some evidence of a bleeding diathesis, such as ecchymoses or heavy menstrual bleeding, though life-threatening bleeding is rare. Approximately 30% of individuals develop spontaneous bleeding, while most only have increased risk for bleeding during hemostatic challenges, such as surgeries, deliveries, or treatment with antiplatelet medications [3].

SNHL is expected to develop in most individuals during their lifetime, reported in about 50% of individuals with a mean age of 33 [3]. Hearing loss is typically bilateral and progressive and is often described by patients as impairing their daily function. Earlier onset hearing loss in MYH9-RD has been associated with more severe deafness [13].

MYH9-RD is associated with progressive glomerular disease in 25–37% of patients [4]. There is significant genotype-phenotype correlation between the location of the pathogenic MYH9 variant and the prevalence and severity of kidney disease, with variants in the head domain associated with a higher prevalence and an earlier age on onset [3, 14]. There is an extremely variable age of progression to end-stage kidney failure (ESKD) in the literature, ranging from 15 to 78 years old [10], sometimes even with significant variability within the same family [4]. Likewise, the current literature does not describe a relationship between gender and MHY9-RD disease prevalence or severity. The cause for this degree of variation is unclear, though the rarity of disease and its autosomal dominant inheritance pattern may make any demographic trends difficult to discern. In our case, patient 1 (female) presented with kidney failure at a much younger age than patient 2 (male).

Typically, the first feature of MYH-RD kidney disease is proteinuria. Hematuria has been associated with MYH9-RD about 50% of the time, possibly secondary to the thrombocytopenia [10]. Kidney pathology often shows FSGS and abnormalities of the glomerular basement membrane [4]. Given the overlap of clinical kidney disease and SNHL, MYH9-RD has often been clinically misdiagnosed as a type IV collagenopathy [2]. One factor that differentiates MYH9-RD from type IV collagenopathies, as exemplified in this family, is the lack of male gender preference and autosomal dominant inheritance pattern, as discussed above.

Additional manifestations of MYH9-RD include early-onset cataracts and elevated liver enzymes. The mean age of cataract development is 37 years old and is typically bilateral and progressive. While elevated transaminases are common in this condition, they typically have been reported to remain stable over time; prior to our case, the condition has not been associated with clinical liver disease [15, 16].

The modeling of the entire human proteome by AlphaFold enables efficient inspection of genetic variants for potential mechanisms of pathogenicity. This technology, when applied in the appropriate context and model confidence is high, is a powerful tool alongside a variant effect predictor like REVEL in interpreting the consequences of genetic variants. AlphaFold gives lower confidence predictions when a protein domain is highly dynamic, exhibits a novel fold, or contains numerous flexible loop regions. However, in the case of this MYH9 variant, p.R424Q, the mutation occurs in the highly conserved myosin motor domain, for which there is experimental evidence in homologs. At position R424, AlphaFold gives a predicted local distance difference test (pLDDT) of 87, indicating high model confidence (70 < pLDDT <90) in the prediction of local backbone and side chain protein geometry.

The p.R424Q variant has previously been reported in two different families with features overlapping with MYH9-RD [2, 6]. In one family, this variant was identified in a 61-year-old man with nephrotic-range proteinuria for 30 years before progressing to ESKD [2]. He developed bilateral SNHL at the age of 50, mild cytopenia without clinical features of a bleeding disorder, giant platelets, and neutrophilic Döhle-like inclusion bodies and mildly elevated liver enzymes (total bilirubin 6 µmol/L, ALT 84 IU/L, AST 43 IU/L). His son, who had the same MYH9 variant, had nephrotic-range proteinuria (5.8 g/d) without hematuria, a serum creatinine of 1.77 mg/dL at time of biopsy, bilateral SNHL starting at age 35, and mild liver dysfunction (total bilirubin 8 µmol/L, ALT 202 IU/L). Biopsy performed in the son at age 23 showed FSGS and a thin glomerular basement membrane. His blood smear was normal. In the other report, this variant was found in two family members with FSGS, with ages of onset of 5 and 10 years old. Additional clinical information about these family members was not provided [6].

Interestingly, variants in the head domain of the protein [14] typically result in significantly more severe thrombocytopenia than those in the tail domain [3, 7]. Both our patients and the previously described family with this head domain variant have a unique presentation of renal-predominant disease with very mild hematological manifestations and no clinical bleeding disorders [2]. However, unlike the other family, our patients lacked clinically evident hearing loss 2 decades after reaching ESKD. These findings may represent a new genotype-phenotype correlation in which this MYH9 head domain variant presents with renal-predominant MYH9-RD.

Patient 2 is the first reported patient with MYH9-RD to have developed cirrhosis. In the literature, patients with elevated liver enzymes were not routinely screened with imaging tests for the presence of steatosis; more than 80% of those who had imaging performed exhibited normal-appearing liver parenchyma [16]. It is notable that patient 2 had mildly elevated transaminases and evidence of hepatic steatosis from the time of transplant evaluation in the setting of type 2 diabetes and obesity. His metabolic syndrome remained difficult to control in the setting of calcineurin inhibitor use post-transplantation. Patient 1 only developed elevated liver enzymes and radiologic evidence of hepatic steatosis 3 years after her kidney transplantation and the start of calcineurin inhibitor therapy, at age 21 and with normal body mass index. Thus, while both patients likely have MYH9-RD-associated elevations in liver enzymes, we cannot prove whether patient 2’s cirrhosis is attributable to this genetic mutation.

This case report demonstrates the important impact that genetic testing can have on the management of patients with idiopathic disease. In particular, the diagnosis of MYH9-RD in patient 1 leads to cascade testing which confirmed the diagnosis in her father as well. This molecular diagnosis also led to appropriate extrarenal screening for both patients based on the other typical clinical features of MYH9-RD. In addition to guiding management by prompting disease-specific screening and avoiding inappropriate therapy, genetic testing can aid in reproductive planning, clarify prognosis and risk for progressive disease including recurrence in the allograft, provide answers for patients regarding the etiology of their disease, and reveal eligibility for current and future clinical trials and treatments.

Strengths of this case report include longitudinal clinical history and provision of a novel protein structural model, leading to a proposed mechanism of disease. Limitations include gaps in certain test results which were precluded by logistical circumstances related to the patients’ illness course and availability.

In summary, we report a case of a father and daughter with a pathogenic missense variant in the head domain of the MYH9 gene (c.1271G>A, p.R424Q) which, due to the loss of a charged residue interrupting hydrogen bonding and π-cation interactions, likely leads to protein misfolding. In our patients, this genetic change led to a renal-predominant MYH9-RD with progression to ESKD, relatively mild macrothrombocytopenia, elevated liver enzymes, and no evidence of cataracts or SNHL. This represents a unique presentation of a head domain variant causing severe kidney disease with mild hematological manifestations. Nephrologists and geneticists should be aware of MHY9-RD as a possible etiology of early-onset idiopathic proteinuric kidney disease, especially in the presence of mild thrombocytopenia, and perform timely genetic testing to guide management for patients and their families.

We gratefully thank the two subjects of this report for sharing their time and clinical information with us. We also express gratitude to Dr. Qais Al-Awqati for his guidance in this analysis.

This study was performed in accordance with the Declaration of Helsinki. Ethical approval was not required for this study in accordance with local/national guidelines. Written informed consent was obtained from patient 1 for herself and on behalf of her father for publication of the details of their medical cases and any accompanying images.

N.S.F. and K.B. have no conflicts of interest. A.B. received support from NIH-NIDDK [K08DK132511], the Gerstner Family Foundation, and the American Society of Nephrology and Kidney Cure Carl W. Gottschalk Research Scholar Award. J.G.N. received support from the NIH-NIDDK [K08DK132511] and the American Society of Nephrology and Kidney Cure’s Harold Amos Medical Faculty Development Award. S.S.-C. is supported by the Department of Defense grant [W81XWH-22-1-0966] and by the National Institute of Health Grant [RC2-DK122397] and is an Associate Editor of Glomerular Diseases. P.A.C. is on the Editorial Board of Glomerular Diseases. Dr. Simone Sanna-Cherchi and Dr. Pietro A. Canetta were members of the journal’s Editorial Board at the time of submission.

This study was not supported by any sponsor or funder.

N.S.F., K.B., and A.B. drafted the manuscript and participated in the conception of the work, reviewing the manuscript critically for important intellectual content, and final approval of the version to be published. J.G.N., S.S.-C., and P.A.C. participated in the conception of the work, reviewing the manuscript critically for important intellectual content, and final approval of the version to be published.

The data supporting the findings of this case report are fully presented within the manuscript. No additional data are available, as the case details are described in the text. Further inquiries may be directed to the corresponding author.