A Deeper Insight into <i>COL4A3</i>, <i>COL4A4</i>, and <i>COL4A5 </i>Variants and Genotype-Phenotype Correlation of a Turkish Cohort with Alport Syndrome

Abstract

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Alport syndrome (AS) is an inherited, rare, progressive kidney disease that affects the eye and ear physiology. Pathogenic variants of &lt;i&gt;COL4A5&lt;/i&gt; account for 85% of all cases, while &lt;i&gt;COL4A3&lt;/i&gt; and &lt;i&gt;COL4A4&lt;/i&gt; account for the remaining 15%. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Targeted next-generation sequencing of the &lt;i&gt;COL4A3&lt;/i&gt;, &lt;i&gt;COL4A4&lt;/i&gt;, and &lt;i&gt;COL4A5&lt;/i&gt; genes was performed in 125 Turkish patients with AS. The patients were compared to 45 controls and open-access population data. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The incidence of AS variants in patients was found as 21.6%. 27 variants were identified as pathogenic/likely pathogenic, 28 as variant of uncertain significance, and 52 as benign/likely benign. We also found 31 novel variants (14 in &lt;i&gt;COL4A3&lt;/i&gt;, 6 in &lt;i&gt;COL4A4&lt;/i&gt;, and 11 in &lt;i&gt;COL4A5&lt;/i&gt;) of which 27 were classified as pathogenic/likely pathogenic. Pathogenic/likely Pathogenic variants were most commonly found in the &lt;i&gt;COL4A5&lt;/i&gt; gene, consistent with the literature. This study contributed novel variants associated with AS to the literature. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Genetic testing is a crucial part for the diagnosis and management of AS. Studies on the genetic etiology of AS are limited for the Turkish population. We believe that this study will contribute to the literature and the clinical decision-making process of patients with AS and emphasize the importance of genetic counseling.

A Novel COL4A5 Pathogenic Variant Joins the Dots in a Family with a Synchronous Diagnosis of Alport Syndrome and Polycystic Kidney Disease

“…Notably, affected individuals who present with proteinuria rather than hematuria are often first diagnosed with steroid-resistant nephrotic syndrome or focal segmental glomerulosclerosis (FSGS). Pathogenic COL4A3-A5 variants contribute to IgA glomerulonephritis [10,11] and are the most common underlying genetic defect in individuals with familial FSGS [12]. Interestingly, polycystic kidney disease (PKD) has been previously reported in few unrelated patients with COL4A4 and COL4A5 variants, occasionally even in the absence of other AS typical features [13,14].…”