Reproductive genetic carrier screening (RGCS) is expanding in both public and private healthcare. The primary aim is to identify carrier status for genetic disorders, inform reproductive decision making and promote reproductive autonomy. As screening panels have increased, the potential for findings with personal health implications rises. We report the prevalence of COL4A3/COL4A4 heterozygous variants within a population undergoing RGCS in a private setting and propose a comprehensive management plan for the ongoing care of this patient cohort. Acknowledging that comprehensive guidelines exist for genetic testing and management of Alport syndrome as a broad patient group, this communication seeks to highlight the increasingly common finding of autosomal dominant Alport syndrome and proposes accessible and practical strategies for the clinicians encountering these patients.

Autosomal dominant Alport syndrome (ADAS), which leads to kidney dysfunction, is primarily associated with heterozygous mutations in COL4A3/4. Mitochondrial disease can also lead to kidney dysfunction. We report a rare case of a 29-year-old woman with ADAS and mitochondrial nephropathy, identified through a genetic analysis, revealing a novel in-frame deletion in COL4A3 and a mitochondrial m.3243A>G mutation. Kidney biopsy revealed basement membrane thinning and mitochondrial nephropathy. Treatment with taurine, arginine, and finerenone improved her proteinuria. This case highlights the complexity of diagnosing genetic kidney diseases and underscores the importance of next-generation sequencing in guiding personalized medicine for optimal and precise management.

Fabry disease (FD) is an X-linked lysosomal disorder caused by GLA mutations, typically associated with glycosphingolipid accumulation and a wide phenotypic spectrum. The p.R112H variant is generally linked to a non-classic predominantly renal phenotype with mild biochemical abnormalities and slow progression. We report the case of a young woman carrying the R112H mutation who exhibited early-onset kidney involvement and unusually rapid progression to end-stage renal disease. Clinical history, serial evaluations, and kidney biopsy findings initially supported a diagnosis of Fabry nephropathy; however, re-evaluation of the native kidney biopsy revealed marked remodeling and multilamellation of the glomerular basement membrane, suggesting Alport-like lesions. Subsequent genetic testing confirmed a heterozygous pathogenic COL4A4 variant (G912R), indicating coexistence of Fabry disease and autosomal dominant Alport syndrome. This dual genetic condition likely accounted for the accelerated decline in kidney function, in contrast with the typically mild phenotype associated with R112H. Our literature review indicates that coexistence of these two inherited nephropathies has not previously been confirmed either histologically or genetically. This case underscores the importance of integrating genetic and ultrastructural assessment in patients with atypical or rapidly progressive renal disease.

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.

Alport syndrome is an inherited glomerular disease that leads to progressive kidney failure, hearing loss, and eye problems. Diagnosis mostly relies on tests of tissue pathology and genetic analysis. This study aims to clarify the role of the COL4A4 c.817-1G > A mutation in Alport syndrome. The COL4A4 gene encodes the α4 chain of type IV collagen, which is a key component of the glomerular basement membrane. Mutations in this gene are strongly linked to Alport syndrome. We collected clinical data from a 12-year-old boy who had "persistent hematuria for 4 years" and performed a renal biopsy, which was pathologically diagnosed as "Alport syndrome". We used high-throughput sequencing technology to conduct whole-exome sequencing (WES) and Sanger sequencing for the patient and his parents. Through bioinformatics analysis, we found that the COL4A4 c.817-1G > A mutation may lead to splicing abnormalities. We extracted RNA from the patients blood and urine samples and used in vivo splicing validation to study the impact of the mutation on mRNA. Our findings show that the COL4A4 c.817-1G > A mutation disrupts mRNA splicing. This mutation affects the splice acceptor site of Intron 13, which is next to Exon 14, causing a 1-bp deletion before Exon 14 and creating a premature stop codon. Consequently, a truncated protein of 273 amino acids is produced, as opposed to the full-length protein of 1,690 amino acids. This finding clarifies the molecular mechanism by which this mutation contributes to Alport syndrome. Our study finds that the COL4A4 c.817-1G > A variant may cause autosomal dominant Alport syndrome. Our research expands the mutation spectrum of Alport syndrome while aiding in genetic counseling and diagnosis for affected patients.