How genomics reclassifies diseases: the case of Alport syndrome

Abstract 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.

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Prevalence of clinical, pathological and molecular features of glomerular basement membrane nephropathy caused by COL4A3 or COL4A4 mutations: a systematic review

Clinical Kidney Journal ◽

10.1093/ckj/sfz176 ◽

2020 ◽

Vol 13 (6) ◽

pp. 1025-1036 ◽

Cited By ~ 3

Author(s):

Andreas Matthaiou ◽

Tsielestina Poulli ◽

Constantinos Deltas

Keyword(s):

Basement Membrane ◽

Alport Syndrome ◽

Autosomal Dominant ◽

Wide Spectrum ◽

Age At Onset ◽

Histological Finding ◽

Basement Membranes ◽

Thin Basement Membrane Nephropathy ◽

Molecular Features ◽

Thin Basement Membrane Disease

Abstract Background Patients heterozygous for COL4A3 or COL4A4 mutations show a wide spectrum of disease, extending from familial isolated microscopic haematuria, as a result of thin basement membranes (TBMs), to autosomal dominant Alport syndrome (ADAS) and end-stage renal disease (ESRD). Many patients are mentioned in the literature under the descriptive diagnosis of TBM nephropathy (TBMN), in which case it actually describes a histological finding that represents the carriers of autosomal recessive Alport syndrome (ARAS), a severe glomerulopathy, as most patients reach ESRD at a mean age of 25 years. Methods We performed a systematic literature review for patients with heterozygous COL4A3/A4 mutations with the aim of recording the spectrum and frequency of pathological features. We searched three databases (PubMed, Embase and Scopus) using the keywords ‘Autosomal Dominant Alport Syndrome’ OR ‘Thin Basement Membrane Disease’ OR ‘Thin Basement Membrane Nephropathy’. We identified 48 publications reporting on 777 patients from 258 families. Results In total, 29% of the patients developed chronic kidney disease (CKD) and 15.1% reached ESRD at a mean age of 52.8 years. Extrarenal features and typical Alport syndrome (AS) findings had a low prevalence in patients as follows: hearing loss, 16%; ocular lesions, 3%; basement membrane thickening, 18.4%; and podocyte foot process effacement, 6.9%. Data for 76 patients from 54 families emphasize extensive inter- and intrafamilial heterogeneity, with age at onset of ESRD ranging between 21 and 84 years (mean 52.8). Conclusions The analysis enabled a comparison of the clinical course of patients with typical ARAS or X-linked AS with those with heterozygous COL4A mutations diagnosed with TBMN or ADAS. Despite the consequence of a potential ascertainment bias, an important outcome is that TBM poses a global high risk of developing severe CKD, over a long follow-up, with a variable spectrum of other findings. The results are useful to practicing nephrologists for better evaluation of patients.

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A Novel Mutation of COL4A3 Presents a Different Contribution to Alport Syndrome and Thin Basement Membrane Nephropathy

American Journal of Nephrology ◽

10.1159/000107666 ◽

2007 ◽

Vol 27 (5) ◽

pp. 538-544 ◽

Cited By ~ 8

Author(s):

Ping Hou ◽

Yuqing Chen ◽

Jiaxiang Ding ◽

Guangtao Li ◽

Hong Zhang

Keyword(s):

Basement Membrane ◽

Alport Syndrome ◽

Novel Mutation ◽

Thin Basement Membrane Nephropathy

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Thin basement membrane disease – literature review

Journal of Medical Science ◽

10.20883/medical.e18 ◽

2015 ◽

Vol 84 (3) ◽

pp. 201-204

Author(s):

Jakub Żurawski

Keyword(s):

Electron Microscope ◽

Basement Membrane ◽

Literature Review ◽

Iga Nephropathy ◽

Glomerular Basement Membrane ◽

Alport Syndrome ◽

Clinical Course ◽

Renal Diseases ◽

Renal Lithiasis ◽

Thin Basement Membrane Disease

Initially, the thin glomerular basement membrane disease was called “a gentle and curable hemorrhagic nephritis”. The thin basement membrane disease has been finally characterized at the beginning of 1970s. This is when the connection between previously clinically described gentle microhematuria and significant thinning of glomerular basement membrane discovered during examination under the electron-microscope has been established. Ultimately, the disease has been described as a condition characterized with a diverse clinical course, usually mild, but sometimes progressive. It is a family conditioned disease, but it also appears sporadically and concerns at least 1% of the population. It has also been stated that it is one of the most frequent renal diseases, enumerated directly after changes caused by infections, hypertension and renal lithiasis. This particular disease is diagnosed more often than IgA nephropathy and Alport syndrome, which are also associated with haematuria or microhematuria.

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A novel CRYBB2 mutation causes autosomal dominant cataract: A report from a Chinese family

European Journal of Ophthalmology ◽

10.1177/1120672120926450 ◽

2020 ◽

pp. 112067212092645

Author(s):

Li Juan Xu ◽

Zhi Gang Lv ◽

Ying Liu ◽

Xiang Xiang Zhang ◽

Yu Xin Cui ◽

...

Keyword(s):

Axial Length ◽

Healthy Subjects ◽

Sanger Sequencing ◽

Autosomal Dominant ◽

Pathogenic Mutation ◽

Chinese Family ◽

Rare Mutation ◽

Pathogenic Variants ◽

Lens Opacities ◽

Generation Sequencing

Purpose This study aimed to examine pathogenic mutation within one Chinese family of five-generations suffering from autosomal dominant cataract. Methods Next-generation sequencing and Sanger sequencing were used to find the pathogenic variants. Results A rare mutation, c.563G > A, in CRYBB2 gene was found in the proband that showed symptom of non-syndromic congenital autosomal dominant cataract. This mutation had been found in all affected individuals and in one healthy infant, but it did not exist between two individuals who did not develop such disease in that family, as well as in 100 healthy subjects who showed no relation with that family. Cataracts in this family varied with different severity of lens opacities and elongation of axial length. Conclusion One missense mutation c.563G > A is reported in the CRYBB2 gene among one Chinese family suffering from early-onset cataract, and associated novel phenotypes are the elongation of axial length and the types of cataract. Our results expand the spectrum of associated phenotypes of CRYBB2 mutation.

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