Alport syndrome (AS), a hereditary kidney disease with a high risk for renal failure, is attributed to pathogenic variants in genes COL4A3, COL4A4, and COL4A5 that encode type IV collagen. Next-generation sequencing (NGS) is increasingly applied to the diagnosis of AS, but complex genotype-phenotype correlation, that is, identifying the significance of variants, is still a huge clinical challenge. In this study, we reported the case of a 27-year-old Chinese woman with a family history of hematuria and proteinuria. Notably, the proband is the only one in her family with renal insufficiency. NGS was performed in this family, and it was revealed that the proband was a compound heterozygote for two variants in the COL4A3 gene: c.2990G>A inherited from her father and c.4981C>T inherited from her mother. We modeled the spatial structure of the corresponding protein and assumed that structural abnormalities led to the breakdown of type IV collagen networks, a major component of the glomerular basement membrane. Thus, the proband was diagnosed with autosomal recessive AS, characterized by severe defects of the glomerular basement membrane. Hence, the proband showed a loss of renal function. This case presentation emphasizes the importance of NGS for AS diagnosis and introduces a novel genotype of AS.

Alport syndrome is a rare genetic condition characterized by kidney disease, hearing impairment, and ocular abnormalities. It exhibits various inheritance patterns involving pathogenic variants in COL4A3, COL4A4, and COL4A5 genes. The phenotypes can range from isolated hematuria with a non-progressive or very slowly progressive course to progressive kidney disease with extrarenal abnormalities. Timely diagnosis of Alport syndrome facilitates the early and effective implementation of treatment, as well as genetic counseling. Here, we report the COL4A3 c.765G > A, p.((=)) mutation in three ethnically Azerbaijani, apparently unrelated, consanguineous families from the village of Algeti in the Marneuli region of Georgia. We speculate that this variant could represent a founder mutation within this population and recommend offering genetic testing to Algeti village residents with persistent hematuria.

Alport syndrome (AS) is a genetic kidney disease of basement membrane collagen disorder accounting for approximately 2% of ESRD patients. Next-generation and whole-exome sequencing methods are increasingly frequently used as an efficient tool not only for the diagnosis of AS but also for the establishment of genotype-phenotype correlation. We herein report the identification of a novel heterozygous missense mutation in COL4A3 gene (c.G3566A: p.G1189E) causing variable phenotypes in an ADAS Family based on the combination of clinical, histologic, pedigree, and genetic sequencing information. The proband is a 48-year-old Chinese woman suffering from persistent subnephrotic proteinuria and intermittent hematuria without renal function impairment over a 10-year time-span. Renal biopsy showed diffuse thin basement membrane and focal interstitial foam cell infiltration. The proband\'s mother progressed to end-stage renal failure and the proband\'s sister presented with subnephrotic proteinuria and intermittent hematuria as well. AS was highly suspected and confirmed by exome sequencing which revealed a novel heterozygous missense mutation in COL4A3 gene (c.G3566A: p.G1189E) in all the affected family members, although their current medical conditions vary significantly. Our present finding emphasizes the significance of next-generation sequencing technology for genetic screening which gives us an accurate clinical diagnosis of ADAS patients. The identification of c.G3566A as a new ADAS-related mutation contributes to both genetic diagnosis of ADAS and further functional study of COL4A3. The variable phenotypes from the same genotype of our case also provide more information to genotype-phenotype correlation study.

Nutcracker syndrome (NCS) is characterized by compression of the left renal vein (LRV) between the aorta and the superior mesenteric artery. While rare, NCS was reported to be accompanied by double inferior vena cava (IVC). We herein report a case of Noonan syndrome (NS) with double IVC who presented with macrohematuria and proteinuria.
The patient was a 23-year-old man, who had been diagnosed with NS due to RIT1 mutation, after showing foamy macrohematuria 3 weeks previously. A physical examination revealed low-set ears and a webbed neck. A urinalysis showed hematuria and proteinuria, and urinary sediments showed more than 100 isomorphic red blood cells per high-power field. His proteinuria and albuminuria concentrations were 7.1 and 4.5 g/g⋅Cr, respectively. Three-dimensional contrast-enhanced computed tomography (CT) showed double IVC and narrowing of the LRV after interflow of the left IVC. The aortomesenteric angle on a sagittal reconstruction of the CT image was 14.7°. Cystoscopy revealed a flow of macrohematuria from the left ureteral opening. On Doppler ultrasonography, there was scant evidence to raise the suspicion of the nutcracker phenomenon. Since severe albuminuria continued, a left kidney biopsy was performed. Light microscopy showed red blood cells in Bowman\'s space and the tubular lumen. Electron microscopy revealed disruption of the glomerular basement membrane (GBM). Vulnerability of the GBM was suspected and a genetic analysis revealed a heterozygous mutation at c.4793 T > G (p.L1598R) in the COL4A3 gene. Screening for coagulation disorders revealed the factor VIII and von Willebrand factor (vWF) values were low, at 47.6 and 23%, respectively. A multimer analysis of vWF showed a normal multimer pattern and he was diagnosed with von Willebrand disease type 1. As the bleeding tendency was mild, replacement of factor VIII was not performed. His macrohematuria and proteinuria improved gradually without treatment, and his urinalysis results have been normal for more than 6 months.
The present case showed macrohematuria and proteinuria due to NCS in NS with double IVC and von Willebrand disease type 1. The macrohematuria and proteinuria originated from glomerular hemorrhage because of vulnerability of the GBM due to COL4A3 mutation.

BACKGROUND: Alport syndrome (ATS) is a rare hereditary disease caused by mutations in genes such as COL4A3, COL4A4, and COL4A5. ATS involves a spectrum of phenotypes ranging from isolated hematuria that is nonprogressive to progressive renal disease with extrarenal abnormalities. Although ATS can be combined with other diseases or syndromes, ATS combined with lupus nephritis has not been reported before.
METHODS: A Chinese family with ATS was recruited for the current study. Clinical characteristics (including findings from renal biopsy) of ATS patients were collected from medical records, and potential causative genes were explored by whole-exome sequencing. A heterozygous substitution in intron 22 of COL4A3 (NM_000091 c.2657-1G>A) was found in the patients, which was further confirmed by quantitative polymerase chain reaction.
CONCLUSIONS: Heterozygous substitution of a COL4A3 gene splice site was identified by whole-exome sequencing, revealing the molecular pathogenic basis of this disorder. In general, identification of pathogenic genes can help to fully understand the molecular mechanism of disease and facilitate precise treatment.

In this issue, Matthews et al. provide a comprehensive review of published cohorts with heterozygous pathogenic variants in COL4A3 or COL4A4, documenting the wide spectrum of the disease. Due to the extreme phenotypes that patients with heterozygous pathogenic variants in COL4A3 or COL4A4 may show, the disease has been referred to in a variety of ways, including \'autosomal dominant Alport syndrome\', \'thin basement membrane disease\', \'thin basement membrane nephropathy\', \'familial benign hematuria\' and \'carriers of autosomal dominant Alport syndrome\'. This confusion over terminology has prevented nephrologists from being sufficiently aware of the relevance of the entity. Nowadays, however, next-generation sequencing facilitates the diagnosis and it is becoming a relatively frequent finding in haematuric-proteinuric nephropathies of unknown origin, even in non-familial cases. There is a need to raise awareness among nephrologists about the disease in order to improve diagnosis and provide better management for these patients.

Kidney transplantation is the treatment of choice in end-stage renal disease due to Alport syndrome (AS). However, the chances of finding an adequate living-related donor in AS are much worse compared to non-heritable conditions. Successful cases of related living-donor transplantation mostly refer to X-linked AS but are rarely reported in genetically confirmed autosomal AS.
We describe the outcome of an exceptional AB0-incompatible kidney donation from father to son in a family with altered COL4A3. While decision-making was based on extensive clinical donor evaluation prior to transplantation, we analyzed the underlying genetic background in retrospect and associated these findings with the phenotype in all available family members. While biallelic COL4A3 variants caused autosomal recessive AS (ARAS) in the son (recipient), heterozygous family members, including the father (donor), showed minimal renal involvement and high-frequency sensorineural hearing impairment later in life indicating mild autosomal dominant Alport syndrome (ADAS). The recipient\'s successful participation in the European and World Transplant Games is a testament to the positive outcome of transplantation.
In summary, living-related donor transplantation may be successful in autosomal AS, provided that thorough clinical and genetic evaluation of potential donors is performed. However, unrelated kidney transplantation should be given priority upon unpredictable genetic risk. Individual genetic variant interpretation is an important component of personalized donor assessment and will help to better predict genetic risk in the future.