title: COL4A4-related nephropathy caused by a novel mutation in a large consanguineous Saudi family.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Electronic address: kramzan@kfshrc.edu.sa.
authors.forename: Khushnooda
authors.initials: K
authors.lastname: Ramzan
authors.affiliation: Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Faiqa
authors.initials: F
authors.lastname: Imtiaz
authors.affiliation: ENT Medical Centre, Riyadh, Saudi Arabia.
authors.forename: Khalid
authors.initials: K
authors.lastname: Taibah
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Samir
authors.initials: S
authors.lastname: Alnufiee
authors.affiliation: Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Akhtar
authors.affiliation: Department of Ophthalmology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Selwa A F
authors.initials: SA
authors.lastname: Al-Hazzaa
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Owain
mesh_terms: D000293:Adolescent; D000328:Adult; D024141:Collagen Type IV / Q000235:genetics*; D003241:Consanguinity; D005260:Female; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009394:Nephritis, Hereditary / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D012529:Saudi Arabia
chemical_list: C466620:COL4A4 protein, human; D024141:Collagen Type IV
keywords: Alport syndrome; COL4A4; Genetic counseling; Hematuria; Mutation; Type IV collagen