Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling.

BACKGROUND Alport syndrome (AS) is a hereditary nephropathy characterized by progressive renal failure, hearing loss and ocular lesions. Numerous mutations of the COL4A5 gene encoding the alpha 5-chain of type IV collagen have been described, establishing the molecular cause of AS. The goal of the present study was to identify the genotype-phenotype correlations that are helpful in clinical counseling. COL4A5-mutations (n=267) in males were analysed including 23 German Alport families. METHODS Exons of the COL4A5 gene were PCR-amplified and screened by Southern blot, direct sequencing or denaturing gradient gel electrophoresis. Phenotypes were obtained by questionnaires or extracted from 44 publications in the literature. Data were analysed by Kaplan-Meier statistics, chi(2) and Kruskal-Wallis tests. RESULTS Genotype-phenotype data for 23 German Alport families are reported. Analysis of these data and of mutations published in the literature showed the type of mutation being a significant predictor of end-stage renal failure (ESRF) age. The patients' renal phenotypes could be grouped into three cohorts: (1) large rearrangements, frame shift, nonsense, and splice donor mutations had a mean ESRF age of 19.8+/-5.7 years; (2) non-glycine- or 3' glycine-missense mutations, in-frame deletions/insertions and splice acceptor mutations had a mean ESRF age of 25.7+/-7.2 years and fewer extrarenal symptoms; (3) 5' glycine substitutions had an even later onset of ESRF at 30.1+/-7.2 years. Glycine-substitutions occurred less commonly de novo than all other mutations (5.5% vs 13.9%). However, due to the evolutionary advantage of their moderate phenotype, they were the most common mutations. The intrafamilial phenotype of an individual mutation was found to be very consistent with regards to the manifestation of deafness, lenticonus and the time point of onset of ESRF. CONCLUSIONS Knowledge of the mutation adds significant information about the progress of renal and extrarenal disease in males with X-linked AS. We suggest that the considerable prognostic relevance of a patient's genotype should be included in the classification of the Alport phenotype.

[1]  P. Marynen,et al.  Differential splicing of COL4A5 mRNA in kidney and white blood cells: A complex mutation in the COL4A5 gene of an alport patient deletes the NC1 domain , 1994, Pediatric Nephrology.

[2]  M. Sanak,et al.  Alport syndrome: a genetic study of 31 families , 1992, Human Genetics.

[3]  E. Ars,et al.  Alport syndrome , 2020, Definitions.

[4]  O. Gross,et al.  Sporadic case of X-chromosomal Alport syndrome in a consanguineous family , 2000, Pediatric Nephrology.

[5]  H. Smeets,et al.  X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. , 2000, Journal of the American Society of Nephrology : JASN.

[6]  D. Vetrie,et al.  Detection of mutations in COL4A5 in patients with Alport Syndrome , 1999, Human mutation.

[7]  T. Shows,et al.  High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing. , 1998, Journal of the American Society of Nephrology : JASN.

[8]  M. Mihatsch,et al.  Ultrastructural and immunohistochemical findings in Alport's syndrome: a study of 108 patients from 97 Italian families with particular emphasis on COL4A5 gene mutation correlations. , 1998, Journal of the American Society of Nephrology : JASN.

[9]  I. Naito,et al.  Topoisomerase I and II consensus sequences in a 17-kb deletion junction of the COL4A5 and COL4A6 genes and immunohistochemical analysis of esophageal leiomyomatosis associated with Alport syndrome. , 1998, American journal of human genetics.

[10]  G. Rizzoni,et al.  Missense mutations in the COL4A5 gene in patients with X‐linked alport syndrome , 1998, Human mutation.

[11]  O. Gross,et al.  Alport syndrome: clinical and genetic correlation in a type-IV collagen disease. , 1997, Contributions to nephrology.

[12]  M. Gregory,et al.  Common ancestry of three Ashkenazi-American families with Alport syndrome and COL4A5 R1677Q , 1997, Human Genetics.

[13]  H. Smeets,et al.  The clinical spectrum of type IV collagen mutations. , 1997, Human mutation.

[14]  C. Antignac,et al.  Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome. , 1996, American journal of human genetics.

[15]  O. Gross,et al.  Use of psoralen-coupled nucleotide primers for screening of COL4A5 mutations in Alport syndrome. , 1996, Kidney international.

[16]  E. Stone,et al.  A mutation causing Alport syndrome with tardive hearing loss is common in the western United States. , 1996, American journal of human genetics.

[17]  A. Ballabio,et al.  X-linked Alport syndrome: an SSCP-based mutation survey over all 51 exons of the COL4A5 gene. , 1996, American journal of human genetics.

[18]  I. Naito,et al.  Relationship between COL4A5 gene mutation and distribution of type IV collagen in male X-linked Alport syndrome. Japanese Alport Network. , 1996, Kidney international.

[19]  R. Trembath,et al.  Identification of 17 mutations in ten exons in the COL4A5 collagen gene, but no mutations found in four exons in COL4A6: a study of 250 patients with hematuria and suspected of having Alport syndrome. , 1996, Journal of the American Society of Nephrology : JASN.

[20]  K. Harano,et al.  The COL4A5 gene in Japanese Alport syndrome patients: spectrum of mutations of all exons. The Japanese Alport Network. , 1996, Kidney international.

[21]  K. Harano,et al.  A single-base mutation in exon 31 converting glycine 852 to arginine in the collagenous domain in an Alport syndrome patient. , 1996, Nephron.

[22]  A. Ballabio,et al.  Major COL4A5 gene rearrangements in patients with juvenile type Alport syndrome. , 1995, American journal of medical genetics.

[23]  F. Endo,et al.  Splicing mutations in the COL4A5 gene in Alport's syndrome: different mRNA expression between leukocytes and fibroblasts. , 1995, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[24]  P. Pignatti,et al.  A novel missense mutation in exon 3 of the COL4A5 gene associated with late‐onset Alport syndrome , 1995, Clinical genetics.

[25]  H. Nishio,et al.  Mutation in alpha 5(IV) collagen chain gene in nonfamilial hematuria. , 1995, Journal of the American Society of Nephrology : JASN.

[26]  C. Antignac.  Molecular genetics of basement membranes: the paradigm of Alport syndrome. , 1995, Kidney international. Supplement.

[27]  P. Marynen,et al.  Severe alport phenotype in a woman with two missense mutations in the same COL4A5 gene and preponderant inactivation of the X chromosome carrying the normal allele. , 1995, The Journal of clinical investigation.

[28]  M. Bobrow,et al.  Detection of 12 novel mutations in the collagenous domain of the COL4A5 gene in Alport syndrome patients , 1995, Human mutation.

[29]  U. Jensen,et al.  A nonsense mutation in the COL4A5 collagen gene in a family with X-linked juvenile Alport syndrome. , 1995, Kidney international.

[30]  F. Endo,et al.  Mutations in the COL4A5 gene in Alport syndrome: a possible mutation in primordial germ cells. , 1994, Kidney international.

[31]  K. Tryggvason,et al.  COL4A5 deletions in three patients with Alport syndrome and posttransplant antiglomerular basement membrane nephritis. , 1994, Journal of the American Society of Nephrology : JASN.

[32]  M. Raghunath,et al.  Delayed triple helix formation of mutant collagen from patients with osteogenesis imperfecta. , 1994, Journal of molecular biology.

[33]  H. Smeets,et al.  Aberrant splicing of the COL4A5 gene in patients with Alport syndrome. , 1994, Human molecular genetics.

[34]  G. Rizzoni,et al.  De-novo COL4A5 gene mutations in Alport's syndrome. , 1994, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[35]  P. Pignatti,et al.  A novel frameshift deletion in type IV collagen α5 gene in a juvenile‐type Alport syndrome patient: An adenine deletion (2940/2943 del A) in exon 34 of COL4A5 , 1994 .

[36]  A. Sessa,et al.  Variability of clinical phenotype in a large Alport family with Gly 1143 Ser change of collagen alpha 5(IV)-chain. , 1994, Nephron.

[37]  K. Tryggvason,et al.  Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. , 1993, The Journal of biological chemistry.

[38]  P. Marynen,et al.  Differential splicing of COL4A5 mRNA in kidney and white blood cells: a complex mutation in the COL4A5 gene of an Alport patient deletes the NC1 domain. , 1993 .

[39]  F. Endo,et al.  Identification of a single base insertion in the COL4A5 gene in Alport syndrome. , 1993, Kidney international.

[40]  M. Nelen,et al.  Identification of four novel mutations in the COL4A5 gene of patients with Alport syndrome. , 1993, Genomics.

[41]  K. Harano,et al.  A splicing mutation in the α5(IV) collagen gene of a family with Alport's syndrome , 1993 .

[42]  M. Gregory,et al.  Mutations in the codon for a conserved arginine-1563 in the COL4A5 collagen gene in Alport syndrome. , 1993, Kidney international.

[43]  K. Tryggvason,et al.  COL4A5 splice site mutation and α5(IV) collagen mRNA in Alport syndrome , 1993 .

[44]  K. Harano,et al.  A splicing mutation in the alpha 5(IV) collagen gene of a family with Alport's syndrome. , 1993, Kidney international.

[45]  K. Tryggvason,et al.  Deletions of the COL4A5 gene in patients with Alport syndrome. , 1992, Kidney international.

[46]  H. Smeets,et al.  Different mutations in the COL4A5 collagen gene in two patients with different features of Alport syndrome. , 1992, Kidney international.

[47]  C. Antignac,et al.  Substitution of arginine for glycine 325 in the collagen alpha 5 (IV) chain associated with X-linked Alport syndrome: characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments. , 1992, American journal of human genetics.

[48]  K. Tryggvason,et al.  Complete amino acid sequence of the human alpha 5 (IV) collagen chain and identification of a single-base mutation in exon 23 converting glycine 521 in the collagenous domain to cysteine in an Alport syndrome patient. , 1992, The Journal of biological chemistry.

[49]  K. Tryggvason,et al.  Mutation in the alpha 5(IV) collagen chain in juvenile-onset Alport syndrome without hearing loss or ocular lesions: detection by denaturing gradient gel electrophoresis of a PCR product. , 1992, American journal of human genetics.

[50]  G. Rizzoni,et al.  De novo mutation in the COL4A5 gene converting glycine 325 to glutamic acid in Alport syndrome. , 1992, Human molecular genetics.

[51]  M. Skolnick,et al.  Identification of mutations in the COL4A5 collagen gene in Alport syndrome. , 1990, Science.

[52]  M. Bobrow,et al.  GENETICS OF CLASSIC ALPORT'S SYNDROME , 1988, The Lancet.

[53]  Alport Ac.  HEREDITARY FAMILIAL CONGENITAL HAEMORRHAGIC NEPHRITIS , 1927 .

[54]  A. Alport.  HEREDITARY FAMILIAL CONGENITAL HAEMORRHAGIC NEPHRITIS , 1927, British medical journal.

[55]  L. Welt,et al.  Diseases of the Kidney , 1905, The Hospital.