Variants in COL4A3 and COL4A4 cause autosomal dominant and recessive Alport syndrome, yet data on their distribution and clinical expression in different populations remain limited. This study investigated genotype-phenotype correlations and the distribution of COL4A3/COL4A4 variants in a Lithuanian Alport syndrome cohort. A total of 221 individuals from Lithuania were analyzed for COL4A3 and COL4A4 variants using either next-generation sequencing or Sanger sequencing in order to assess variant distribution and associated clinical features. Only individuals with pathogenic, likely pathogenic, or uncertain significance variants were included. Fifty-two individuals (38 index cases) with pathogenic, likely pathogenic, or variants of uncertain significance were identified, as follows: forty-eight were heterozygous, four had autosomal recessive, and four had digenic Alport syndrome. COL4A3 variants were found in 9.5% (21/221) and COL4A4 in 17.6% (39/221). Among the 28 identified variants, 18 were novel. Glycine substitutions (n = 8) were the most frequent and associated with worse kidney outcomes and increased hearing abnormalities. Hematuria was diagnosed significantly earlier than proteinuria (p = 0.05). Most individuals with autosomal dominant Alport syndrome had normal kidney function (eGFR > 90 mL/min/1.73 m2), while those with autosomal recessive Alport syndrome had more severe disease. Kidney failure occurred in 2/4 (50%) autosomal recessive Alport syndrome and 2/48 (4%) autosomal dominant Alport syndrome cases. A significant inverse correlation was found between eGFR and age in proteinuric individuals (r = -0.737; p = 0.013). This study expands knowledge of Alport syndrome in the Lithuanian population and contributes novel variant data to the global Alport syndrome genetic database. Alport syndrome is characterized by kidney manifestations, sensorineural hearing loss (SNHL), and ocular manifestations. In the absence of treatment, kidney disease progresses from microhematuria to proteinuria, progressive kidney insufficiency, and end-stage kidney disease (ESKD) in most males with X-linked Alport syndrome (XLAS), and in most males and females with autosomal recessive Alport syndrome (ARAS). Progressive SNHL is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In females with XLAS and individuals with autosomal dominant Alport syndrome (ADAS), ESKD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare. The molecular diagnosis of Alport syndrome is established in a proband with suggestive findings and a pathogenic variant(s) in COL4A3, COL4A4, or COL4A5 identified by molecular genetic testing. Kidney biopsy, skin biopsy (in some individuals with XLAS), or clinical diagnostic criteria may be used to establish the diagnosis in those without access to genetic testing or those with uninformative results. Treatment of manifestations: Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to delay onset of ESKD; standard treatment of hypertension; kidney transplantation for ESKD. Potential living related donors must be evaluated carefully to avoid nephrectomy in an affected individual. Hearing aids as needed for SNHL; cataract removal as needed; in those with deletions of COL4A5 extending into intron 2 of COL4A6, surgical intervention for symptomatic leiomyomas as needed. Surveillance: Evaluation by a nephrologist including urinalysis, assessment of kidney function, and blood pressure every six to 12 months; monthly monitoring of at-risk transplant recipients for development of anti-glomerular basement membrane antibody-mediated glomerulonephritis for the first year post transplant; audiologic evaluation every one to two years beginning at age six to seven years; ophthalmology evaluation for ocular abnormalities every one to two years beginning in adolescence in males with a COL4A5 truncating pathogenic variant and in persons with ARAS. Agents/circumstances to avoid: Drink adequate fluids as dehydration may accelerate the progression of nephropathy. Protection of corneas from minor trauma in those with recurrent corneal erosions. Minimize exposure to loud noise. Evaluation of relatives at risk: Evaluate at-risk family members in order to identify as early as possible those who would benefit from initiation of treatment either by molecular genetic testing if the pathogenic variant(s) in the family are known or urinalysis and blood pressure if the pathogenic variant(s) in the family are not known. COL4A5-related Alport syndrome is inherited in an X-linked manner (XLAS). COL4A3- and COL4A4-related Alport syndrome are inherited in an autosomal dominant (ADAS) or autosomal recessive (ARAS) manner. Digenic Alport syndrome is caused by pathogenic variants in more than one Alport syndrome-related gene: typically pathogenic variants in both COL4A3 and COL4A4 (on the same or on opposite chromosomes) or, more rarely, a pathogenic variant in COL4A5 in addition to a pathogenic variant in COL4A3 or COL4A4. XLAS: The risk to sibs of a male proband depends on the genetic status of the mother: if the mother of the proband has a COL4A5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. The risk to the sibs of a female proband depends on the genetic status of the parents: if the mother of the proband has a COL4A5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%; if the father of the proband has a COL4A5 pathogenic variant, he will transmit it to all of his daughters and none of his sons. Males and females who inherit the pathogenic variant will be affected. ARAS: If both parents are known to be heterozygous for a COL4A3 or COL4A4 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants (and having ARAS), a 50% chance of being heterozygous (and at risk for ADAS), and a 25% chance of inheriting neither of the familial pathogenic variants. ADAS: If a parent of the proband is affected and/or is known to have the COL4A3 or COL4A4 pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. The severity of clinical manifestations may vary greatly among heterozygous family members; some heterozygotes may be asymptomatic and some may develop ESKD. Digenic Alport syndrome: The risk to sibs depends on the involved genes, the location of the pathogenic variants (i.e., on the same or on opposite chromosomes) in families segregating pathogenic variants in COL4A3 and COL4A4, and the sex of the proband (in families segregating pathogenic variants in COL4A5 and COL4A3 or COL4A4). Once the Alport syndrome-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Autosomal dominant Alport syndrome (ADAS) is an uncommon diagnosis and is often missed in patients with chronic kidney disease of unknown origin unless specific genetic testing is performed. It results from heterozygous mutations in the COL4A3 and COL4A4 genes. The clinical presentation is variable but generally milder than that of X-linked or autosomal recessive Alport syndrome. In this article, we present the case of a 78-year-old man who was diagnosed with ADAS during evaluation in a nephrology clinic. We also discuss the condition and the challenges related to the terminology surrounding Alport syndrome.

Background/Objectives: Alport syndrome (AS) predominantly presents with X-linked inheritance worldwide. However, the epidemiological landscape remains poorly characterized, particularly among ethnic minority groups like the Roma minority in Slovakia. Our study aimed to investigate the inheritance patterns of AS in this region and determine whether a distinct pattern predominates. Methods: Selective genetic screening for pathogenic variants previously occurring in Slovakia was performed. Samples from patients with persistent (familial) hematuria ± hearing loss who had not yet undergone biopsy or genetic testing were analyzed by high-resolution melting analysis. The prevalence of AS per million (pm) population was calculated by adding information on patients with previously confirmed AS. Results: Twenty-five new cases of ARAS, one digenic form, and two cases of XLAS were identified by screening. In total, we collected information on 46 patients with genetically or bioptically confirmed AS in the region of eastern Slovakia, corresponding to a prevalence of 29 pm population. The c.1598G>A (p.Gly533Asp) pathogenic variant of the collagen type IV alpha 4 chain, which follows an autosomal recessive inheritance pattern, was the most prevalent variant that was exclusively confirmed in Roma patients (n = 35), suggesting a founder effect. Within the Roma community, the prevalence of ARAS (the most prevalent inheritance pattern) corresponds to 133 pm of the Roma population, based on midpoint population estimates. Conclusions: Our findings demonstrate a unique genetic profile of AS in the Roma population, characterized by a high prevalence of ARAS, with implications for genetic counseling and screening strategies.

A 20-year-old male patient diagnosed with chronic renal failure owing to autosomal recessive Alport syndrome underwent kidney transplant, with his mother as the donor. After transplant, the patient's renal function was enhanced; however, owing to preoperative nonadherence, he required sedation and mechanical ventilation. Sedation and mechanical ventilation were discontinued on postoperative day 5. The next day, the patient experienced impaired consciousness. On day 7, magnetic resonance imaging of the head revealed posterior reversible encephalopathy syndrome. Tacrolimus was immediately discontinued, and steroid pulse therapy was initiated. The patient gradually gained consciousness and reached preoperative levels by day 10. Autosomal recessive Alport syndrome, a rare form of Alport syndrome, constitutes 15% of all cases. This report documents a case of tacrolimus-associated posterior reversible encephalopathy syndrome after living donor kidney transplant.

Alport syndrome involves chronic progressive kidney failure and extrarenal organ damage caused by COL4A3, COL4A4, and COL4A5 mutations. We initially discerned a COL4A3 splicing mutation via next-generation sequencing. Next, we used bioinformatics, renal biopsy pathology, and an in vitro minigene experiment. Complementary analysis of clinical data was carried out, and we explored the expression and function of the variants to verify their pathogenicity. A splicing mutation (c.687 + 1G > T) in COL4A3 was found in a Chinese family. Bioinformatics analysis revealed its impact on splicing, causing a translational frameshift, which was confirmed by an in vitro minigene assay. The proband's glomerular basement membrane displayed reduced type IV collagen α3, α4, and α5 chains, with some absent, suggesting disruption of collagen IV trimers in the glomerular basement membrane, potentially damaging the glomerular filtration barrier. We present a novel finding of a previously unreported c.687 + 1G > T mutation in COL4A3 that disrupts transcription and translation, impairing α3α4α5 (IV) chain formation, altering the integrity of the glomerular basement membrane, causing hereditary Alport syndrome. This discovery enriches the genetic map of Alport syndrome, aiding in clinical genetic guidance, and enhancing the efficacy of prenatal testing.