INTRODUCTION: Collagen type IV related nephropathies are due to the defects in 
collagen IV genes COL4A3, COL4A4, or COL4A5 and comprise a spectrum of 
phenotypes ranging from Alport Syndrome (AS) to its mild variants, termed as 
familial haematuria or thin basement membrane nephropathy. Classical AS is a 
progressive renal disease presenting with a triad of progressive hematuric 
nephritis and typical extra-renal complications, such as sensorineural hearing 
loss (SNHL) and variable ocular anomalies. The mode of inheritance in AS is 
X-linked in 85%, autosomal recessive in 15%, and autosomal dominant in rare 
cases.
OBJECTIVES: This study aims to identify underlying mutation in multiple 
individuals from a large consanguineous Saudi family with inherited nephropathy, 
including our index patient who manifested all the features of classical AS.
PATIENTS AND METHODS: Patients were diagnosed by nephrologists and clinical 
geneticists. All the individuals underwent clinical, audiological and 
ophthalmological evaluation. Blood samples were collected after written informed 
consent. DNA extraction, homozygosity mapping and PCR amplification followed 
standard methodologies.
RESULTS: The disease locus was mapped to 2q36.3, where both COL4A3 and COL4A4 
reside. Sanger sequencing of COL4A3 and COL4A4 revealed an underlying novel 
homozygous disease-causing COL4A4 mutation (c.2420delG; p.G807fsX60) in the 
affected proband. Considerable phenotypic variability segregating with this 
COL4A4 mutation in our study family is documented. The homozygous mutants were 
manifesting end-stage renal disease (ESRD) in their adolescence, while the 
heterozygous carrier members were presenting with considerable phenotypic 
heterogeneity ranging from intermittent hematuria to late onset ESRD. In 
addition, there is a relatively severe involvement of the ear (SNHL) and eye in 
the homozygotes than the heterozygotes. Fertility problems were also noted in 
both of the homozygous females.
CONCLUSION: Identification of the causative mutation is an efficient strategy 
for conclusive molecular diagnosis in the patients and to establish 
genotype/phenotype correlation. It is important to study and evaluate 
asymptomatic carriers, to predict prognosis of the disease and to obviate the 
need for another renal biopsy in at-risk related family members. While an 
accurate genetic diagnosis of AS provides valuable information for genetic 
counseling in the extended family members, it can also facilitate future 
prenatal diagnosis and planning for pre-implantation genetic diagnosis.