Clinical utility gene card for: Alport syndrome

Hertz, Jens Michael; Thomassen, Mads; Storey, Helen; Flinter, Frances

doi:10.1038/ejhg.2011.237

Cited by 41 publications

(40 citation statements)

References 6 publications

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“…15 Genetic testing is at least 90% sensitive for X-linked disease. 16 Alport syndrome must be distinguished from the other causes of inherited hematuria and renal failure, inherited renal disease and hearing loss, retinal flecks, and GBM lamellation (Table 2). Hematuria is not typical of the most common familial forms of pediatric renal failure, namely FSGS and nephronophthisis.…”

Section: Diagnosis Of Alport Syndromementioning

confidence: 99%

“…16 Clinical features depend mainly on the mutation's location and genotype. About 50% result in a stop codon either directly or downstream, and 40% of mutations are missense.…”

Section: Genetic Testingmentioning

confidence: 99%

“…About 50% result in a stop codon either directly or downstream, and 40% of mutations are missense. 16 Large deletions and rearrangements, nonsense mutations, and carboxy terminal missense mutations typically result in early-onset renal failure, hearing loss, and ocular abnormalities, 15,29 whereas amino terminal missense mutations are often associated with late-onset renal failure without the extrarenal features. The likelihood of early-onset renal failure in affected males can also be predicted from the effect of the mutation in other affected male relatives.…”

Section: Genetic Testingmentioning

confidence: 99%

“…Autosomal recessive inheritance is confirmed when there are two COL4A3 or two COL4A4 pathogenic mutations or the GBM lacks the collagen IV a3, a4, and a5 chains but the a5 chain persists in the Bowman capsule and the distal tubular and the epidermal membrane. 21,61 Genetic Testing Genetic testing is useful to confirm the diagnosis of autosomal recessive Alport syndrome 16 when it is suspected on the basis of clinical features, family history, or renal immunohistochemistry. Fewer mutations have been described for recessive than for X-linked disease, and too few are known for genotype-phenotype correlations.…”

Section: Autosomal Recessive Alport Syndromementioning

confidence: 99%

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Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy

Savige

Gregory

Groß³

et al. 2013

Journal of the American Society of Nephrology

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282

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Few prospective, randomized controlled clinical trials address the diagnosis and management of patients with Alport syndrome or thin basement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18 recommendations are based on Level D (Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles-National Health Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees-U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstration of its mode of inheritance; the need to identify and follow all affected members of a family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and consideration of genetic testing to exclude X-linked Alport syndrome in some individuals with thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.

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Section: Diagnosis Of Alport Syndromementioning

confidence: 99%

“…16 Clinical features depend mainly on the mutation's location and genotype. About 50% result in a stop codon either directly or downstream, and 40% of mutations are missense.…”

Section: Genetic Testingmentioning

confidence: 99%

Section: Genetic Testingmentioning

confidence: 99%

Section: Autosomal Recessive Alport Syndromementioning

confidence: 99%

See 2 more Smart Citations

Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy

Savige

Gregory

Groß³

et al. 2013

Journal of the American Society of Nephrology

Self Cite

303

282

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“…40 Variant pathogenicity was assessed using Alamut software (versions 1.5 and 2.0; Interactive Biosoftware), which includes tools AlignGVGD, SIFT, and Polyphen,interrogation of dbSNPand the Swissprot databases, interspecies conservation, variant domain location and Grantham distance due to the effect of the mutation, a Google web search, and splicing algorithms SpliceSiteFinder-like, MaxEntScan, NNSplice, and GeneSplicer. Pathogenicity of variants was determined in accordance with the Clinical Molecular Genetics Society best practice guidelines.…”

Section: Variant Nomenclature and Classificationmentioning

confidence: 99%

COL4A3/COL4A4 Mutations and Features in Individuals with Autosomal Recessive Alport Syndrome

Storey

Savige

Sivakumar

et al. 2013

Journal of the American Society of Nephrology

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127

110

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Alport syndrome is an inherited disease characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities. Autosomal recessive Alport syndrome is suspected in consanguineous families and when female patients develop renal failure. Fifteen percent of patients with Alport syndrome have autosomal recessive inheritance caused by two pathogenic mutations in either COL4A3 or COL4A4. Here, we describe the mutations and clinical features in 40 individuals including 9 children and 21 female individuals (53%) with autosomal recessive inheritance indicated by the detection of two mutations. The median age was 31 years (range, 6-54 years). The median age at end stage renal failure was 22.5 years (range, 10-38 years), but renal function was normal in nine adults (29%). Hearing loss and ocular abnormalities were common (23 of 35 patients [66%] and 10 of 18 patients [56%], respectively). Twenty mutation pairs (50%) affected COL4A3 and 20 pairs affected COL4A4. Of the 68 variants identified, 39 were novel, 12 were homozygous changes, and 9 were present in multiple individuals, including c.2906C.G (p.(Ser969*)) in COL4A4, which was found in 23% of the patients. Thirty-six variants (53%) resulted directly or indirectly in a stop codon, and all 17 individuals with early onset renal failure had at least one such mutation, whereas these mutations were less common in patients with normal renal function or late-onset renal failure. In conclusion, patient phenotypes may vary depending on the underlying mutations, and genetic testing should be considered for the routine diagnosis of autosomal recessive Alport syndrome.

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Urine-derived podocytes-lineage cells: A promising tool for precision medicine in Alport Syndrome

et al. 2017

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Alport Syndrome (ATS) is a rare genetic disorder caused by collagen IV genes mutations, leading to glomerular basement membrane damage up to end-stage renal disease. Podocytes, the main component of the glomerular structure, are the only cells able to produce all the three collagens IV alpha chains associated with ATS and thus, they are key players in ATS pathogenesis. However, podocytes-targeted therapeutic strategies have been hampered by the difficulty of non-invasively isolating them and transcripts-based diagnostic approaches are complicated by the inaccessibility of other COL4 chains-expressing cells. We firstly isolated podocyte-lineage cells from ATS patients' urine samples, in a non-invasive way. RT-PCR analysis revealed COL4A3, COL4A4, and COL4A5 expression. Transcripts analysis on RNA extracted from patient's urine derived podocyte-lineage cells allowed defining the pathogenic role of intronic variants, namely one mutation in COL4A3 (c.3882+5G>A), three mutations in COL4A4 (c.1623+2T>A, c.3699_3706+1del, c.2545+143T>A), and one mutation in COL4A5 (c.3454+2T>C). Therefore, our cellular model represents a novel tool, essential to unequivocally prove the effect of spliceogenic intronic variants on transcripts expressed exclusively at a glomerular level. This process is a key step for providing the patient with a definite molecular diagnosis and with a proper recurrence risk. The established system also opens up the possibility of testing personalized therapeutic approaches on disease-relevant cells.

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Clinical utility gene card for: Alport syndrome

Cited by 41 publications

References 6 publications

Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy

Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy

COL4A3/COL4A4 Mutations and Features in Individuals with Autosomal Recessive Alport Syndrome

Urine-derived podocytes-lineage cells: A promising tool for precision medicine in Alport Syndrome

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