Alport: Renaming an Extended Clinical Spectrum

Alport syndrome was first described in the 1920s by Cecil Alport who identified the link between hearing loss and macroscopic hematuria.1 Subsequent studies demonstrated the presence of ocular defects including anterior lenticonus and retinal flecks,2 and on the basis of this clinical triad, Alport syndrome was reported to have a prevalence ranging from one in approximately 5000–50,000 individuals.3 With the advent of electron microscopy of kidney biopsies in the 1970s, characteristic abnormalities of the glomerular basement membrane (GBM) were described, including GBM thinning and a distinctive basket-weave appearance.4 These findings led to the use of pathology-based descriptors, such as basement membrane nephropathy. By the 1980s, Alport syndrome was known to have both X-linked and autosomal modes of inheritance. In the 1990s, molecular genetic analyses identified three genes that associated with the clinical features of Alport syndrome: COL4A3 and COL4A4 on chromosome 2 and COL4A5 on the X-chromosome.5,6 The proteins they encode form the type IV collagen α-3,4,5 network, which is a critical component of basement membranes in the kidneys, cochleas, and eyes.7 Terms to describe the mode of inheritance of Alport syndrome emerged, and molecular descriptions including collagenopathy and collagen IV nephropathy arose from the realization that structural defects in collagen networks underpinned the pathology. However, these descriptors are not easily understood by nonspecialists, are not always specific, and are unpopular with patients. The emergence of population genomic studies in the 2020s provided a fresh perspective on Alport syndrome, defining the frequency of pathogenic/likely pathogenic (P/LP) variants in the Alport genes and the associated range of clinical features. These studies revealed a prevalence of Alport variants that far exceeded previous estimates, with one in approximately 100 individuals harboring heterozygous P/LP variants in COL4A3 or COL4A4 and one in approximately 2300 individuals having P/LP variants in COL4A5.8 This high frequency raised the question about Alport variants presenting a risk factor for other kidney phenotypes, and examples of Alport variants coexisting with IgA nephropathy, C3 glomerulopathy, and APOL1 nephropathy have been reported, although the mechanisms of how these variants predispose to other kidney phenotypes have not been systematically investigated. The timing/severity of clinical features associated with Alport variants ranges from early/mild to advanced (Figure 1). The most penetrant kidney phenotype is persistent yet sometimes intermittent microscopic hematuria and, at this stage of the disease, kidney cysts may occur and a kidney biopsy may show a thin GBM. Depending on the Alport variants involved, sensorineural hearing loss can occur early between the age of 5–10 years, and this should prompt evaluation of kidney function. In early/mild stages, eye findings are absent or limited to fleck retinopathy that does not impair vision, and temporal retinal thinning has been reported.9Figure 1: Proposed naming convention for conditions associated with Alport gene variants. The Alport spectrum is the overarching classification with two subcategories: Alport risk and Alport syndrome. The dyadic naming convention pairs these subcategories with the name of the affected Alport gene, and the risk of developing advanced clinical features depends on the genetic variant. In all individuals with Alport risk or Alport syndrome, the progression of the kidney features can be slowed by early kidney protective treatment (e.g., ACE inhibitors), and therefore, all individuals should have lifelong kidney surveillance. ACE, angiotensin-converting enzyme; GBM, glomerular basement membrane; IFTA, interstitial fibrosis and tubular atrophy.Persistent proteinuria is a sign of kidney disease progression, and irrespective of the genetic variant, affected individuals should start on angiotensin-converting enzyme inhibitor therapy because this has been shown to extend kidney survival.3,10 The rate of GFR decline is associated with both genetic and environmental factors such as smoking, diet, and exercise. With features of progression, a kidney biopsy may show FSGS, lamination of the GBM, interstitial fibrosis, and tubular atrophy. Moderate sensorineural hearing loss and corneal erosions are also features of progression. Advanced features include kidney failure, severe sensorineural hearing loss, anterior lenticonus, and cataracts. At the point of genetic diagnosis, the prognostic classification of individuals into those with anticipated clinical features of progression is determined by the genetic variant. Male and female patients with two affected copies of COL4A3 and/or COL4A4 (autosomal recessive), as well as male patients with an affected COL4A5 gene (X-linked), have approximately 100% risk of developing kidney failure during their lifetime, and approximately 80% will have hearing loss. Approximately 15%–30% of female patients with an affected COL4A5 gene (X-linked) will develop kidney failure, with most having hearing loss.3 The clinical spectrum for individuals with a single affected COL4A3 or COL4A4 gene (autosomal dominant) is broad, ranging from persistent microscopic hematuria throughout life to kidney failure in approximately 3%, although very few experience early onset hearing loss.3 The reasons for this variability in kidney disease progression in individuals with a single affected COL4A3 or COL4A4 gene are not yet fully understood but are likely related to genetic modifiers and environmental influences. The extended spectrum of clinical phenotypes associated with Alport variants has prompted many questions around naming of the condition. Do individuals with an Alport variant and only persistent microscopic hematuria have Alport syndrome? Or should this name be reserved for those with or predicted to have severe kidney, hearing, and eye features? Should pathology terms such as thin basement membranes be used, without confirmation with a kidney biopsy? And should the naming include collagen IV as the molecular basis of the condition? The challenge of disease naming is not unique to Alport syndrome. Recognizing the need for standardization in the fields of genomic research and clinical genetics, the Clinical Genome Resource, in partnership with the Monarch Disease Ontology and Online Mendelian Inheritance in Man, established the Disease Naming Advisory Committee (DNAC). This interdisciplinary group was established to develop a consistent approach to naming and categorizing genetic conditions.11 A key recommendation from the DNAC is the adoption of a paired or dyadic naming convention, which links the gene name to a descriptive term. The descriptor needs to be specific for the condition and can be a clinical feature, a more general clinical term, or an eponym. This recommendation ensures that disease entities have unambiguous, easily recognizable terms that communicate relevant information. For monogenic conditions, this strategy also reflects the causal relationship between abnormal gene function and the disease phenotype or risk of developing the phenotype. The inclusion of inheritance patterns in the phenotypic label is typically not needed and generally discouraged in the DNAC recommendations. The Alport community, comprising a diverse group of stakeholders including patients, clinicians, and researchers from around the world, have collaborated over the past 5 years to review disease naming recommendations and to develop an improved naming system. Here we report a strong global consensus to retain the eponym “Alport” while adhering to appropriate clinical, genetic, and scientific naming conventions. As a result, “The Alport spectrum” was proposed as the overarching classification term. This term balances scientific accuracy with patient preference and clinical utility, and under this overarching term, we propose two subcategories: 1. Alport risk: individuals with or predicted to have a mild or moderate Alport phenotype primarily affecting the kidney, but with only a slightly greater risk of kidney failure compared with the general population and usually late in life. 2. Alport syndrome: individuals with or predicted to have severe kidney features leading eventually to kidney failure, plus hearing and/or eye features. The dyadic naming convention allows for further specification on the basis of pairing the above subcategories with the affected gene(s), which we suggest are referred to as Alport genes: 1. Individuals with or predicted to have a mild or moderate kidney phenotype Alport risk-COL4A3 (one affected copy of COL4A3) Alport risk-COL4A4 (one affected copy of COL4A4) 2. Individuals with or predicted to have moderate to severe clinical features Alport syndrome-COL4A5 (one affected copy of COL4A5) Alport syndrome-COL4A3 + COL4A3 (two affected copies of COL4A3) Alport syndrome-COL4A4 + COL4A4 (two affected copies of COL4A4) With these primary names, additional details can be communicated as required, for example: Primary name: Alport syndrome-COL4A5. Additional details: male, X-linked, pathogenic missense variant, Gly1492Asp, CKD stage 4, sensorineural hearing loss, corneal erosions. The adoption of this inclusive naming system acknowledges the spectrum of experiences among individuals living with Alport variants, while highlighting overlapping genetic and clinical features. By reframing what has been known for generations as “Alport syndrome” into a broader “Alport spectrum,” we also promote a more comprehensive understanding of the condition. Ultimately, our goal is to ensure that every individual affected by Alport variants has timely access to accurate diagnosis and appropriate treatment.