Clinical Kidney Journal, 2020, vol. 13, no. 6, 933–935 doi: 10.1093/ckj/sfaa170 Advance Access Publication Date: 16 September 2020 Editorial Comment EDITORIAL COMMENT How genomics reclassifies diseases: the case of Alport syndrome 1,2 1,2 3 Roser Torra , Monica Furlano and Elisabet Ars 1 Department of Nephrology, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Barcelona, Spain, 2Medicine Department-Universitat Autónoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain and 3Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autónoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain Correspondence to: Roser Torra; E-mail: rtorra@fundacio-puigvert.es 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. Keywords: Alport, autosomal dominant Alport syndrome, COL4A3, COL4A4, familial haematuria, thin basement membrane disease It is well known that genomics can allow the reclassification of entity, such as autosomal dominant tubulointerstitial disease genetic diseases, and inherited kidney diseases are no excep- (ADTKD) followed by the name of the causative gene, e.g. tion. Many renal diseases have been named after the physicians ADTKD-UMOD (uromodulin) or ADTKD-MUC1 (mucin 1). who first identified them, as in the case of Fabry disease, von Giving descriptive names to new diseases is usually much Hippel–Lindau syndrome, Bartter syndrome and Liddle syn- easier than changing old names in the light of new findings. In drome, among others. For some other diseases, a new name the case of patients with heterozygous pathogenic variants in more descriptive of the entity has generally replaced the origi- COL4A3 or COL4A4, use of the traditional term Alport syndrome nal name; examples include ‘tuberous sclerosis complex’ in- is contentious, but a new term has yet to emerge. While Alport stead of ‘Pringle-Bourneville disease’ and ‘immunoglobulin A syndrome as traditionally described fits very well into X-linked nephropathy’ instead of ‘Berger’s disease’. For nephropathies (XLAS) and autosomal recessive (ARAS) forms, this does not caused by newly identified genes, the disease term frequently hold true for patients with heterozygous variants in COL4A3 originates from the gene itself plus a brief description of the or COL4A4. In this issue of CKJ, Matthews et al. provide a Received: 7.7.2020; Editorial decision: 9.7.2020 C The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 933 934 | R. Torra et al. systematic review of published cases with heterozygous patho- patients to receive early antiproteinuric treatment, specific genic variants in COL4A3 or COL4A4. The terms ‘autosomal treatment when available, and adequate follow-up; increased dominant Alport syndrome’ (ADAS), ‘thin basement membrane knowledge of the disease will facilitate the development of disease, ‘thin basement membrane nephropathy,’ ‘familial be- prognostic tools and therefore differentiation between those nign hematuria’ and ‘carriers of ARAS’ have all been used to patients who will progress to ESKD and those who will not; and designate this entity. This confusing terminology has prevented it will enable patients to get in touch with patient advocacy and many diagnoses and stopped many patients from receiving support groups. early renin–angiotensin–aldosterone system inhibition, among The use of next-generation sequencing for routine analy- other measures. Also, the variation in names leads to bias in ses of suspected cases of familial nephropathy is of seminal published series, as patients are selected on the basis of the relevance to the identification of ADAS patients who would presence of the clinical features associated with the name of otherwise elude any diagnosis of kidney disease. But not only the disease specified in the individual article in question. family cases should be studied; expression of the disease is As shown in the review article by Matthews et al., carriers of highly variable in patients with heterozygous pathogenic var- heterozygous pathogenic variants of COL4A3 or COL4A4 present iants of COL4A3 or COL4A4, meaning that very extreme phe- with a wide spectrum of clinical manifestations, ranging from notypes may coexist within a single family. This may prevent haematuria (or even bland urine sediment) to end-stage kidney recognition of the fact that a genetic disease runs in the disease (ESKD) (Figure 1). Although two recent consensus docu- family. Also, families may be unaware that relatives have ments have continued to use the term ‘thin basement mem- haematuria or chronic kidney disease, and even if they brane disease’ [1, 2], this designation no longer seems suitable, are aware of it, the condition may have been attributed to age, primarily because it is a pathological term and this finding can hypertension, diabetes, etc. Therefore ADAS should be be found in the early stages of XLAS and ARAS, as well as in considered in the differential diagnosis of patients with other glomerular diseases. For the same reason, focal segmental persistent glomerular haematuria, even without a family glomerulosclerosis is not used for patients with heterozygous history. pathogenic variants of COL4A3 or COL4A4 and advanced kidney When nephrologists think of Alport syndrome, most will an- disease [3–5]. The name ‘familial benign hematuria’ is old fash- ticipate some extrarenal manifestations, such as sensorineural ioned, as we now know that some of these patients may de- deafness and ocular anomalies, but, as shown by Matthews et al., these findings are very uncommon in patients with hetero- velop ESKD, indicating that this is far from being a ‘benign’ zygous pathogenic variants of COL4A3 or COL4A4. disorder. Moreover, it makes little sense that different affected The review by Matthews et al., and hopefully the future pub- members of a single family can be considered to have ‘different lication of findings in more cohorts, will raise awareness of this diseases’ when all share the same single mutation, or that a sin- ‘not so rare’ disease and allow precise diagnosis and follow-up gle patient may be given different names for his/her disease for a significant number of kidney patients who have been over the course of his/her lifetime. undiagnosed or misdiagnosed to date. With all these terminological issues, Alport syndrome is at least the second most common inherited kidney disease after autosomal dominant polycystic kidney disease (ADPKD) [6]. It FUNDING may be even more prevalent than ADPKD if one takes into ac- The author’s research is funded by the Instituto de Salud count the fact that many of these individuals show only micro- Carlos III/Fondo Europeo de Desarrollo Regional (FEDER) haematuria. Of course, in terms of health impact, the most funds, RETIC REDINREN RD16/0009 FIS FEDER FUNDS (PI15/ relevant subgroup comprises individuals with heterozygous pathogenic variants of COL4A3 or COL4A4 who develop ESKD. 01824, PI16/01998, PI18/00362, PI19/01633). Today there is a need for the nephrologist to be aware of the existence of these diseases for many reasons: this will reduce CONFLICT OF INTEREST STATEMENT the number of patients with ‘nephropathy of unknown etiology’ None declared. The results presented in this article have not who reach ESKD; it will allow genetic counselling and evalua- been published previously in whole or part. tion of at-risk relatives; patients will be able to participate in Alport syndrome clinical trials; early diagnosis will allow REFERENCES ESKD 1. Kashtan CE, Ding J, Garosi G et al. Alport syndrome: a unified Clinical features classification of genetic disorders of collagen IV a345: a posi- Renal failure Proteinuria tion paper of the Alport Syndrome Classification Working Extrarenal Microhematuria features Group. Kidney Int 2018; 93: 1045–1051 Asymptomatic 2. Savige J, Ariani F, Mari F et al. Expert consensus guidelines for Disease severity Pattern of inheritance the genetic diagnosis of Alport syndrome. Pediatr Nephrol – + Males XLAS, males and females ARAS 2019; 34: 1175–1189 – Females XLAS + 3. Malone AF, Phelan PJ, Hall G et al. 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