Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene.
BACKGROUND
Alport syndrome is a clinically and genetically heterogeneous nephropathy. The majority of cases are transmitted as an X-linked semidominant condition due to COL4A5 mutations. In this form males are more severely affected than females. Less than 10% of cases are autosomal recessive due to mutation in either COL4A3 or COL4A4. In this rarer form, both males and females are severely affected. Only two cases of autosomal-dominant Alport syndrome have been reported, one due to a COL4A3 mutation and the other due to a COL4A4 mutation. Because of the paucity of the reported families, the natural history of autosomal-dominant Alport syndrome is mostly unknown.


METHODS
Four families with likely autosomal-dominant Alport syndrome were investigated. COL4A3 and COL4A4 genes were analyzed by denaturing high-performance liquid chromatography (HPLC). Automated sequencing was performed to identify the underlying mutation.


RESULTS
Two families had a mutation in the COL4A4 gene and two in the COL4A3. Accurate clinical evaluation of family members showed interesting results. Affected individuals (22 persons) had a wide range of phenotypes from end-stage renal disease (ESRD) in the fifth decade to a nonprogressive isolated microhematuria. Finally, three heterozygous individuals (90, 22 and 11 years old, respectively) were completely asymptomatic.


CONCLUSIONS
This paper demonstrated that patients affected by autosomal-dominant Alport syndrome have a high clinical variability. Moreover, a reduced penetrance of about 90% (3 of 25) may be considered for the assessment of recurrence risk during genetic counseling of these families.
Pescucci
Chiara
C
Medical Genetics, Department of Molecular Biology, University of Siena, Siena, Italy.
Mari
Francesca
F
Longo
Ilaria
I
Vogiatzi
Paraskevi
P
Caselli
Rossella
R
Scala
Elisa
E
Abaterusso
Cataldo
C
Gusmano
Rosanna
R
Seri
Marco
M
Miglietti
Nunzia
N
Bresin
Elena
E
Renieri
Alessandra
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001324:Autoantigens / Q000235:genetics*; D002648:Child; D024141:Collagen Type IV / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007668:Kidney / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009394:Nephritis, Hereditary / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype
D001324:Autoantigens; C466620:COL4A4 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain