Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy

Weber, Stefanie; Sträßer, Katja; Rath, Sabine; Kittke, Achim; Beicht, Sonja; Alberer, Martin; Lange-Sperandio, Bärbel; Hoyer, Peter F.; Benz, Marcus R.; Ponsel, Sabine; Weber, Lutz T.; Klein, Hanns‐Georg; Hoefele, Julia

doi:10.1007/s00467-015-3302-4

Cited by 38 publications

(31 citation statements)

References 49 publications

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“…Due to the high population frequency of LOAN, genetics clinics and laboratories examine more patients who progress to chronic renal failure or ESRD because of inheritance of LOAN than patients who inherit classical AS. Similar findings concerning the high risk of LOAN patients progressing to renal function decline of variable degree, have been reported by several groups, who referred to these patients as having inherited TBMN …”

Section: Discussionsupporting

confidence: 88%

Frequent COL4 mutations in familial microhematuria accompanied by later‐onset Alport nephropathy due to focal segmental glomerulosclerosis

et al. 2017

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Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

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Section: Discussionsupporting

confidence: 88%

Frequent COL4 mutations in familial microhematuria accompanied by later‐onset Alport nephropathy due to focal segmental glomerulosclerosis

et al. 2017

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“…This substitution likely interferes with normal folding of the triple helical protomers, leading to an abnormal Type IV collagen. Another missense variation (Gly631Val) affecting the same codon has previously been reported as one of the compound heterozygous variants . In a study of 40 patients with ARAS, out of all mutations, 37% resulted in a missense change, 35% were frameshift mutations, 18% were nonsense mutations, 6% were small deletions/duplications, 4% were splicing mutations.…”

Section: Discussionmentioning

confidence: 97%

Successful renal transplantation in a family with a novel mutation in COL4A3 gene and autosomal recessive Alport syndrome

Girimaji

Nada

et al. 2020

Nephrology

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Alport syndrome (AS) is an inherited disorder of basement membranes caused by mutations affecting specific proteins of the type IV collagen family, presenting with nephropathy and extrarenal manifestations such as sensorineural deafness and ocular anomalies.Ten percentage to 15% of the patients with AS have autosomal recessive (ARAS) due to mutation in either COL4A3 or COL4A4 gene. We report a novel mutation in the COL4A3 gene in an Indian family with ARAS. The above-mentioned genetic anomaly was a missense variation in exon 26 of the COL4A3 gene (chr2:228137797G>A; c.1891G>A) that resulted in the amino acid substitution of Arginine for Glycine at codon 631 (p.Gly631Arg) that was present in the heterozygous state in the asymptomatic parents and homozygous state in the male offspring who presented with early-onset end-stage renal disease, lenticonus and hearing loss. The patient (male offspring) underwent successful renal transplantation with his mother as a donor.

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“…Of note, collagen (COL4A) mutations are present in families with Alport syndrome (85% of Alport syndrome is caused by mutations of COL4A5), and are also present in some families with familial FSGS, sporadic FSGS, and thin basement membrane disease. 374,375 Overall, the severity of nephropathy in Alport syndrome is variable. Many males with X-linked Alport syndrome will develop ESKD before the age of 40 years.…”

Section: Apolipoprotein L1 (Apol1) Risk Allelesmentioning

confidence: 99%

Survival in Living Kidney Donors: An Australian and New Zealand Cohort Study Using Data Linkage

Mata

Clayton

Kelly

et al. 2020

Transplantation Direct

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The 2017 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors is intended to assist medical professionals who evaluate living kidney donor candidates and provide care before, during and after donation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach and guideline recommendations are based on systematic reviews of relevant studies that included critical appraisal of the quality of the evidence and the strength of recommendations. However, many recommendations, for which there was no evidence or no systematic search for evidence was undertaken by the Evidence Review Team, were issued as ungraded expert opinion recommendations. The guideline work group concluded that a comprehensive approach to risk assessment should replace decisions based on assessments of single risk factors in isolation. Original data analyses were undertaken to produce a "proof-in-concept" risk-prediction model for kidney failure to support a framework for quantitative risk assessment in the donor candidate evaluation and defensible shared decision making. This framework is grounded in the simultaneous consideration of each candidate's profile of demographic and health characteristics. The processes and framework for the donor candidate evaluation are presented, along with recommendations for optimal care before, during, and after donation. Limitations of the evidence are discussed, especially regarding the lack of definitive prospective studies and clinical outcome trials. Suggestions for future research, including the need for continued refinement of long-term risk prediction and novel approaches to estimating donation-attributable risks, are also provided.

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Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy

Cited by 38 publications

References 49 publications

Frequent COL4 mutations in familial microhematuria accompanied by later‐onset Alport nephropathy due to focal segmental glomerulosclerosis

Frequent COL4 mutations in familial microhematuria accompanied by later‐onset Alport nephropathy due to focal segmental glomerulosclerosis

Successful renal transplantation in a family with a novel mutation in COL4A3 gene and autosomal recessive Alport syndrome

Survival in Living Kidney Donors: An Australian and New Zealand Cohort Study Using Data Linkage

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