title: Autosomal recessive Alport syndrome: an in-depth clinical and molecular analysis of five families.
abstract: BACKGROUND
  Alport syndrome (ATS) is a progressive inherited nephropathy characterized by irregular thinning, thickening and splitting of the glomerular basement membrane (GBM) often associated with hearing loss and ocular symptoms. ATS has been shown to be caused by COL4A5 mutations in its X-linked form and by COL4A3 and COL4A4 mutations in its autosomal forms.
  
  
  METHODS
  Five families with a suspicion of ATS were investigated both from a clinical and molecular point of view. COL4A3 and COL4A4 genes were analysed by DHPLC. Automated sequencing was performed to identify the underlying mutation.
  
  
  RESULTS
  Molecular analysis indicated that in all 5 cases the correct diagnosis was autosomal recessive ATS. In three families in which parental consanguinity clearly pinpointed to autosomal recessive ATS, we found COL4A4 homozygous mutations in two of them and COL4A3 homozygous mutation in the other one. In the remaining two families a differential diagnosis including X-linked ATS, autosomal recessive ATS and thin basement membrane nephropathy was considered. The molecular analysis demonstrated that the probands were genetic compounds for two different mutations in the COL4A4 gene pinpointing to the correct diagnosis of autosomal recessive ATS.
  
  
  CONCLUSIONS
  A clinical evaluation of probands and their relatives of the five families carrying mutations in either the COL4A3 or the COL4A4 gene was carried out to underline the natural history of the autosomal recessive ATS. In addition, this paper stresses the complexity of the clinics and genetics of ATS and how a correct diagnosis is based on a combination of: (i) an in-depth clinical investigation; (ii) a detailed formal genetic analysis; (iii) a correct technical choice of the gene to be investigated; (iv) a correct technical choice of the family member to be included in the mutational screening. A correct diagnosis is the basis for an appropriate genetic counselling dealing with both the correct prognosis and the accurate recurrence risk for the patients and family members.
authors.affiliation: Department of Molecular Biology, University of Siena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Longo
authors.forename: Elisa
authors.initials: E
authors.lastname: Scala
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
authors.forename: Rossella
authors.initials: R
authors.lastname: Caselli
authors.forename: Chiara
authors.initials: C
authors.lastname: Pescucci
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Mencarelli
authors.forename: Caterina
authors.initials: C
authors.lastname: Speciale
authors.forename: Marisa
authors.initials: M
authors.lastname: Giani
authors.forename: Elena
authors.initials: E
authors.lastname: Bresin
authors.forename: Domenica Angela
authors.initials: DA
authors.lastname: Caringella
authors.forename: Zvi-Uri
authors.initials: ZU
authors.lastname: Borochowitz
authors.forename: Komudi
authors.initials: K
authors.lastname: Siriwardena
authors.forename: Ingrid
authors.initials: I
authors.lastname: Winship
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Ilaria
authors.initials: I
authors.lastname: Meloni
mesh_terms: D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002851:Chromatography, High Pressure Liquid; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D000939:Epitopes; D005260:Female; D005838:Genotype; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; D024141:Collagen Type IV; D000939:Epitopes; C057112:type IV collagen alpha3 chain; D004247:DNA