Guidelines for Genetic Testing and Management of Alport Syndrome

Savige, Judy; Lipska‐Ziętkiewicz, Beata S.; Watson, E.; Hertz, Jens Michael; Deltas, Constantinos; Mari, Francesca; Hilbert, Pascale; Plevová, Pavlína; Byers, Peter H.; Čerkauskaitė, Agnė; Gregory, Martin C.; Čerkauskienė, Rimantė; Ljubanović, Danica Galešić; Becherucci, Francesca; Errichiello, Carmela; Massella, Laura; Aiello, Valeria; Lennon, Rachel; Hopkinson, Louise; Koziell, Ania; Lungu, Adrian; Rothe, Hansjörg; Hoefele, Julia; Zacchia, Miriam; Martić, Tamara Nikuševa; Gupta, Asheeta; Eerde, Albertien van; Gear, Susie; Landini, Samuela; Palazzo, Viviana; Al‐Rabadi, Laith; Claes, Kathleen; Corveleyn, Anniek; Hoof, Evelien Van; Geel, Micheel van; Williams, Maggie; Ashton, Emma; Belge, Hendica; Ars, Elisabet; Bierżyńska, Agnieszka; Gangemi, Concetta; Renieri, Alessandra; Storey, Helen; Flinter, Frances

doi:10.2215/cjn.04230321

Cited by 74 publications

(91 citation statements)

References 79 publications

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“…The discoveries of the α3, α4, and α5 chains of collagen IV set the foundation for unraveling the mystery of Alport syndrome and development of therapy [34–40]. Over the preceding 30 years, sequences of cognate genes COL4A3, COL4A4, and COL4A5 were determined and shown to harbor nearly two thousand pathogenetic variants that cause GBM dysfunction [1,2 ▪▪ ,3,4 ▪▪ ]. In parallel, advances were made in understanding the structure and assembly of chains into a complex collagen IV α345 scaffold, as summarized in [5,39,41].…”

Section: Discussionmentioning

confidence: 99%

Prospective collagen IVα345 therapies for Alport syndrome

Boudko

Pokidysheva

Hudson

2022

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of reviewIn Alport syndrome, over 1,700 genetic variants in the COL4A3, COL4A4, and COL4A5 genes cause the absence or malfunctioning of the collagen IVα345 scaffold – an essential component of the glomerular basement membrane (GBM). Therapies are limited to treatment with Angiotensin-Converting enzyme (ACE) inhibitors to slow progression of the disease. Here, we review recent progress in therapy development to replace the scaffold or restore its function.Recent findingsMultiple approaches emerged recently for development of therapies that target different stages of production and assembly of the collagen IVα345 scaffold in the GBM. These approaches are based on (1) recent advances in technologies allowing to decipher pathogenic mechanisms that underlie scaffold assembly and dysfunction, (2) development of DNA editing tools for gene therapy, (3) RNA splicing interference, and (4) control of mRNA translation.SummaryThere is a growing confidence that these approaches will ultimately provide cure for Alport patients. The development of therapy will be accelerated by studies that provide a deeper understanding of mechanisms that underlie folding, assembly, and function of the collagen IVα345 scaffold.

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Section: Discussionmentioning

confidence: 99%

Prospective collagen IVα345 therapies for Alport syndrome

Boudko

Pokidysheva

Hudson

2022

Current Opinion in Nephrology &Amp; Hypertension

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“…In our study three individuals aged 14–41, from three different families, had digenic variants in these genes. According to the recent guidelines for Genetic Testing and Management of Alport Syndrome, digenic inheritance may be associated with more severe phenotypes including kidney impairment ( 37 ). However, in our study none of individuals with digenic variants regardless of the variant type (missense and splicing changes) reached KF.…”

Section: Discussionmentioning

confidence: 99%

Identification of 27 Novel Variants in Genes COL4A3, COL4A4, and COL4A5 in Lithuanian Families With Alport Syndrome

et al. 2022

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Introduction:Alport syndrome (AS) is an inherited disorder characterized by hematuria, proteinuria, and kidney function impairment, and frequently associated with extrarenal manifestations. Pathogenic variants in COL4A5 usually cause X-linked Alport syndrome (XLAS), whereas those in the COL4A3 or COL4A4 genes are associated with autosomal dominant (AD) or recessive (AR) inheritance. To date, more than 3000 different disease-causing variants in COL4A5, COL4A3, and COL4A4 have been identified. The aim of this study was to evaluate the clinical and genetic spectrum of individuals with novel, pathogenic or likely pathogenic variants in the COL4A3-A5 genes in a previously unstudied cohort.MethodsIn this study molecular analysis by next generation sequencing (NGS) was performed on individuals from a Lithuanian cohort, with suspected AS. The presence of AS was assessed by reviewing clinical evidence of hematuria, proteinuria, chronic kidney disease (CKD), kidney failure (KF), a family history of AS or persistent hematuria, and specific histological lesions in the kidney biopsy such as thinning or lamellation of the glomerular basement membrane (GBM). Clinical, genetic, laboratory, and pathology data were reviewed. The novelty of the COL4A3-A5 variants was confirmed in the genetic variant databases (Centogene, Franklin, ClinVar, Varsome, InterVar). Only undescribed variants were included in this study.ResultsMolecular testing of 171 suspected individuals led to the detection of 99 individuals with 44 disease causing variants including 27, previously undescribed changes, with the frequency of 9/27 (33,3%) in genes COL4A5, COL4A3 and COL4A4 equally. Three individuals were determined as having digenic AS causing variants: one in COL4A3 and COL4A4, two in COL4A4 and COL4A5. The most prevalent alterations in genes COL4A3-5 were missense variants (n = 19), while splice site, frameshift, unknown variant and stop codon changes were detected more in genes COL4A4 and COL4A5 and accounted for 3, 3, 1 and 1 of all novel variants, respectively.ConclusionGenotype-phenotype correlation analysis suggested that some variants demonstrated intra-familial phenotypic variability. These novel variants represented more than half of all the variants found in a cohort of 171 individuals from 109 unrelated families who underwent testing. Our study expands the knowledge of the genetic and phenotypic spectrum for AS.

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“…It is important to avoid the use of immunosuppressive therapy on these patients because this would be ineffective and potentially harmful. Consistent with these observations, genetic testing should be obtained in all patients with biopsy-proven FSGS or steroid resistant nephrotic syndrome ( 6 ).…”

Section: Natural History and Prognosismentioning

confidence: 95%

“…Genetic testing in AS is proposed for patients who have persistent dysmorphic hematuria for longer than 6 months; persistent proteinuria >0.5 g/g, family history of hematuria or kidney disease; sensorineural hearing loss with hematuria; lenticonus, fleck retinopathy or temporal retinal thinning; biopsy-proven focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome; GBM lamellation; chronic kidney disease of unknown etiology with hematuria and familial IgA glomerulonephritis. Genetic testing is also recommended in first-degree relatives of people with known pathogenic variants in COL4A3-COL4A5 genes ( 6 ).…”

Section: Classificationmentioning

confidence: 99%

“…In patients with AS, graft survival rates are equal or better compared to those seen in patients with other causes of ESKD. It is recommended that family members who are COL4A3 and COL4A4 heterozygotes not be considered for kidney donation ( 6 ). There is evidence from individuals with hematuria or heterozygous pathogenic COL4A3 or COL4A4 variants who acted as kidney donors who developed worsening kidney function or proteinuria over time ( 16 – 18 ).…”

Section: Kidney Transplantationmentioning

confidence: 99%

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Novel Therapies for Alport Syndrome

et al. 2022

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Alport syndrome (AS) is a hereditary kidney disease associated with proteinuria, hematuria and progressive kidney failure. It is characterized by a defective glomerular basement membrane caused by mutations in type IV collagen genes COL4A3/A4/A5 which result in defective type IV collagen α3, α4, or α5 chains, respectively. Alport syndrome has three different patterns of inheritance: X-linked, autosomal and digenic. In a study of CKD of unknown etiology type IV collagen gene mutations accounted for the majority of the cases of hereditary glomerulopathies which suggests that AS is often underrecognized. The natural history and prognosis in patients with AS is variable and is determined by genetics and environmental factors. At present, no preventive or curative therapies exist for AS. Current treatment includes the use of renin-angiotensin-aldosterone system inhibitors which slow progression of kidney disease and prolong life expectancy. Ramipril was found in retrospective studies to delay the onset of ESKD and was recently demonstrated to be safe and effective in children and adolescents, supporting that early initiation of Renin Angiotensin Aldosterone System (RAAS) blockade is very important. Mineralocorticoid receptor blockers might be favorable for patients who develop “aldosterone breakthrough.” While the DAPA-CKD trial suggests a beneficial effect of SGLT2 inhibitors in CKD of non-metabolic origin, only a handful of patients had Alport in this cohort, and therefore conclusions can't be extrapolated for the treatment of AS with SGLT2 inhibitors. Advances in our understanding on the pathogenesis of Alport syndrome has culminated in the development of innovative therapeutic approaches that are currently under investigation. We will provide a brief overview of novel therapeutic targets to prevent progression of kidney disease in AS. Our review will include bardoxolone methyl, an oral NRf2 activator; lademirsen, an anti-miRNA-21 molecule; sparsentan, dual endothelin type A receptor (ETAR) and angiotensin 1 receptor inhibitor; atrasentan, oral selective ETAR inhibitor; lipid-modifying agents, including cholesterol efflux transporter ATP-binding cassette A1 (ABCA1) inducers, discoidin domain receptor 1 (DDR1) inhibitors and osteopontin blocking agents; the antimalarial drug hydroxychloroquine; the antiglycemic drug metformin and the active vitamin D analog paricalcitol. Future genomic therapeutic strategies such as chaperone therapy, genome editing and stem cell therapy will also be discussed.

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Guidelines for Genetic Testing and Management of Alport Syndrome

Cited by 74 publications

References 79 publications

Prospective collagen IVα345 therapies for Alport syndrome

Prospective collagen IVα345 therapies for Alport syndrome

Identification of 27 Novel Variants in Genes COL4A3, COL4A4, and COL4A5 in Lithuanian Families With Alport Syndrome

Novel Therapies for Alport Syndrome

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