COL4A3/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome

Mutations in the COL4A5 gene result in X-linked Alport syndrome, homozygous or compound heterozygous mutations in COL4A3 or COL4A4 are responsible for autosomal recessive Alport syndrome, and heterozygous mutations in COL4A3 or COL4A4 cause autosomal dominant Alport syndrome or benign familial hematuria. Recently, the existence of a digenic inheritance in Alport syndrome has been demonstrated. We here report heterozygous COL4A3 and COL4A4 digenic mutations in cis responsible for benign familial hematuria. Using bioinformatics analyses and pedigree verification, we showed that COL4A4 c.1471C>T and COL4A3 c.3418 + 1G>T variants in cis are pathogenic and co-segregate with the benign familial hematuria. This result suggests that COL4A3 and COL4A4 digenic mutations in cis mimicking an autosomal dominant inheritance should be considered as a novel inheritance pattern of benign familial hematuria, although the disease-causing mechanism remains unknown.

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MO046NGS PANEL PERFORMANCE IN THE DIAGNOSIS OF HEREDITARY RENAL DISEASE IN SOUTHERN SPAIN

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab080.0018 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

María del Mar Del Águila García ◽

Antonio M Poyatos Andújar ◽

Ana Isabel Morales García ◽

Margarita Martínez Atienza ◽

Susana García Linares ◽

...

Keyword(s):

Kidney Disease ◽

Renal Disease ◽

Polycystic Kidney Disease ◽

Genetic Study ◽

Alport Syndrome ◽

Autosomal Dominant ◽

Kidney Diseases ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney ◽

Hereditary Renal Disease

Abstract Background and Aims Hereditary renal disease (HRD) is still underdiagnosed: although we know aspects related to autosomal dominant polycystic kidney disease (ADPKD), we know little about the incidence and prevalence of other entities such as Alport syndrome. Altogether, HRD can represent 15% of individuals undergoing renal replacement therapy (RRT) or could even be higher. The advancement of genetics at the healthcare level let to achieve accurate and early renal diagnoses, as well as the incorporation of genetic counseling to families, all of which will result in better management of the disease in its initial stages and the possibility of offering reproductive options that avoid transmission to offspring. Our objective is to know the performance offered by the implementation of the ERH panel through Next Generation Sequencing (NGS) in our healthcare area. Method Observational-descriptive study of 259 probands (141 men / 118 women), mean age of 46 years (30 pediatric / 123 over 50 years), with chronic kidney disease and suspected hereditary cause attended in the specialized consultation of our centers from October 2018 to October 2020. The DNA extracted from leukocytes obtained by venipuncture was processed with Nephropathies Solution version 3 panel (SOPHiA Genetics) according to the manufacturer's protocol. This panel covers the coding regions and splicing junctions of 44 HRD-related genes such as nephrotic syndromes, polycystic kidney diseases, Bartter syndromes, Alport syndrome, CAKUT or tubulopathies (table 1). The sequencing of the libraries was done in a MiSeq (Illumina Inc), the bioinformatic analysis of the data and annotation of variants was performed using the SOPHiA DDM 5.8.0.3 software, and the revision of variants by consulting the main databases (ClinVar, Exac, HGMD, NCBI, PKD Foundation, LOVD). Results The panel was informative (pathogenic or probably pathogenic) in 80/259 patients (31%) and 56/259 cases (21.66%) of variants of uncertain significance (VSI) were detected. Autosomal dominant polycystic kidney disease accounted for 76.2% of the variants identified (56.2% PKD1, 20% PKD2), following Alport syndrome with 15% and the alterations in the PKHD1 gene associated with renal polycystic disease in its recessive form with about 4% (Figure 1). We have also identified a case of autosomal dominant tubulointerstitial kidney disease associated with the UMOD gene that was not suspected until the genetic study was performed. We highlight that 45% (36/80) of the variants identified as responsible for the renal disease are not yet described. Overall, the most prevalent type of mutation is that which produces displacement in the reading frame or frameshift (Figure 2). Individually, frameshift is the most frequent alteration in PKD1, PKD2 and COL4A5, while for PKHD1, COL4A3 and COL4A4 it is missense. Conclusion Our NGS HRD panel a) offers an adequate diagnostic performance at the healthcare level, with definitive results in 1 out of 3 cases and has also allowed the performance of many carrier studies among family members b) is able of diagnosing the most frequent disease, ADPKD and Alport syndrome, as well as unresolved or poorly characterized cases, and c) opens the horizon for new diagnoses, all without increasing costs by outsourcing services. All this makes the genetic study of renal pathology a useful and efficient strategy. These results encourage us to enhance the resources in this area that we consider to be of strategic value.

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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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Should We Diagnose Autosomal Dominant Alport Syndrome When There Is a Pathogenic Heterozygous COL4A3 or COL4A4 Variant?

Kidney International Reports ◽

10.1016/j.ekir.2018.08.002 ◽

2018 ◽

Vol 3 (6) ◽

pp. 1239-1241 ◽

Cited By ~ 12

Author(s):

Judy Savige

Keyword(s):

Alport Syndrome ◽

Autosomal Dominant

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Common consultations

10.1093/med/9780199557509.003.0003 ◽

2017 ◽

Author(s):

Helen V. Firth ◽

Jane A. Hurst

Keyword(s):

Support Groups ◽

Alport Syndrome ◽

Autosomal Dominant ◽

Androgen Insensitivity Syndrome ◽

Clinical Approach ◽

Adrenal Hyperplasia ◽

Polycystic Kidney ◽

Hereditary Spastic Paraplegias ◽

Autosomal Dominant Polycystic Kidney ◽

Leigh Encephalopathy

This chapter presents some of the disorders more commonly seen in a genetics clinic from achondroplasia to autosomal dominant polycystic kidney disease, Alport syndrome, androgen insensitivity syndrome, Angelman syndrome, Beckwith–Wiedemann syndrome, congenital adrenal hyperplasia, glaucoma, haemochromatosis, hereditary spastic paraplegias, Leigh encephalopathy, Marfan’s syndrome, Noonan syndrome, and many others. It gives an explanation of the clinical approach, the history, the examination, the investigation, and the diagnosis and lists the support groups.

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MYH9 and renal disease

10.1093/med/9780199592548.003.0342_update_001 ◽

2018 ◽

Author(s):

Neil Turner ◽

Bertrand Knebelmann

Keyword(s):

Renal Disease ◽

Alport Syndrome ◽

Autosomal Dominant ◽

Cell Structure ◽

Myosin Ii ◽

Giant Platelets ◽

The Past ◽

Sensorineural Hearing Impairment ◽

Muscle Myosin ◽

Proteinuric Renal Disease

MYH9 encodes one of three heavy chain isoforms for the non-muscle myosin II (NM II) molecule. NM II is involved in cell structure and shape and motility. Myosin II is very widely expressed but MYH9 is highly expressed in podocytes. MYH9 diseases are characterized by various combinations of autosomal dominant progressive, proteinuric renal disease, giant platelets with low platelet counts, progressive sensorineural hearing impairment, granulocyte inclusions, and in some patients also cataracts. Although the eponyms Epstein and Fechtner have been given to MYH9 renal syndromes, there is a spectrum of manifestations of MYH9 diseases that do not correlate perfectly with genotype. They are best described as MYH9-associated renal disease. The occurrence of progressive deafness and renal failure led to this condition being considered an Alport syndrome variant in the past, but phenotype as well as molecular genetics clearly separate the disorders.

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