Novel COL4A3 synonymous mutation causes Alport syndrome coexistent with immunoglobulin A nephropathy in a woman:A case report

BACKGROUND Alport syndrome(AS)is an inherited disease of the glomerular basement membrane caused by mutations in genes encodingα3,α4,orα5 chains of type IV collagen.It manifests with hematuria or proteinuria,which is often accompanied by hearing impairments and ocular abnormalities.Histopathologically,AS shows mesangial proliferation and sometimes incidental immunoglobulin A(IgA)deposition.Hematuria or proteinuria is also a common presentation in patients with IgA nephropathy that makes it difficult to differentially diagnose AS and IgA nephropathy solely based on these clinical and pathological features.CASE SUMMARY Herein,we present the case of a 59-year-old female patient who was admitted to our hospital with persistent microscopic hematuria and occasional proteinuria that had lasted for>2 years.This patient had a familial history of renal disease and was diagnosed with autosomal dominant AS(ADAS)and IgA nephropathy based on the findings of renal biopsy as well as genetic testing performed using whole-exome sequencing,which suggested that the patient carried a novel heterozygous variation(c.888G>A:p.Gln296Gln)in the COL4A3 gene that enriches the mutation spectrum of ADAS.The proband received an angiotensin receptor blocker therapy after a definitive diagnosis was established.After one year of therapy,a significant reduction in proteinuria was observed.The number of microscopic red blood cells per high-power field decreased to one-quarter of the baseline levels.Renal function also maintained well during the follow-up.CONCLUSION Our case highlights the significance of performing kidney biopsy and genetic testing in the diagnosis of AS and familial IgA nephropathy.

Ocular manifestations of Alport syndrome

AIMTo analyze the clinical manifestation of Alport syndrome, especially the ocular features.

Alport syndrome combined with lupus nephritis in a Chinese family:A case report

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.CASE SUMMARY 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.CONCLUSION Heterozygous substitution of a COL4A3 gene splice site was identified by wholeexome 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.

Temporal retinal thinning might be an early diagnostic indicator in male pediatric X-linked Alport syndrome

AIM: To evaluate temporal retinal thinning changes in retinal layers using spectral-domain optical coherence tomography(SD-OCT) in pediatric X-linked Alport syndrome(XLAS) patients.METHODS: A retrospective case-control study. SDOCT scans of pediatric patients diagnosed with XLAS and age-and sex-matched healthy control participants were reviewed. Automated segmentation of SD-OCT scans was induced to analyze the retinal thickness(RT) of different layers. The temporal thinning index(TTI) was calculated for each layer and compared between the patients and the control group.RESULTS: Forty-three pediatric XLAS patients and 60 healthy controls were included. Temporal retinal thinning was present in 33 patients(76.74%), while 28 patients(65.11%) had severe pathological temporal retinal thinning and 5 patients(11.63%) had moderate thinning. The temporal inner sector RT(P<0.0001), the temporal outer sector RT(P<0.0001), and the nasal outer sector RT(P=0.0211) were significantly thinner in the XLAS male patients. The TTI of the total retina was significantly higher in the XLAS group than in the control group(P<0.0001). The TTI of the inner retina layers(P<0.0001), ganglion cell layer(P<0.0001), inner plexiform layer(P<0.0001), inner nuclear layer(P<0.0001), and outer nuclear layer(P<0.0001) were significantly higher in the XLAS group. The central RT of the XLAS group was significantly thinner than that of the control group(P<0.0001).CONCLUSION: Temporal retinal thinning appears early in XLAS patients, especially in male patients. The thinningis mainly caused by structural abnormalities of the inner retina. This suggests that temporal retinal thinning could be helpful for the early diagnosis and follow-up of XLAS with noninvasive SD-OCT examination.

Identification of a novel COL4A5 mutation in the proband initially diagnosed as Ig AN from a Chinese family with X-linked Alport syndrome

Alport syndrome(AS) is a hereditary progressive nephropathy characterized by hematuria, ultrastructural lesions of the glomerular basement membrane, ocular lesions and sensorineural hearing loss. Germline mutations of COL4 A5 are associated with X-linked AS with an extreme phenotypic heterogeneity. Here, we investigated a Chinese family with Alport syndrome. The proband was a 9-year-old boy with hematuria and proteinuria. Based on the test results of renal biopsy and immunofluorescence,the proband was initially diagnosed as Ig A nephropathy and the treatment was recommended accordingly. Meanwhile, we found that the treatment outcome was poor. Therefore, for proper clinical diagnosis and appropriate treatment, targeted exome-based next-generation sequencing has been undertaken. We identified a novel hemizygous single nucleotide deletion c.1902 del A in COL4 A5 gene. Segregation analysis identified that this novel mutation is co-segregated among the affected family members but absent in unaffected family members. The clinical diagnosis of the proband was revised as AS accompanied by Ig A nephropathy,which has been rarely reported. Our findings demonstrated the significance of the application of Genetic screening, expanded the mutation spectrum of COL4 A5 associated AS patients with atypical renal phenotypes and provided a good lesson to be learned from our detour during the diagnosis.