Kidney Res Clin Pract.  2016 Jun;35(2):96-101. 10.1016/j.krcp.2016.02.003.

PKD2 mutation in an Iranian autosomal dominant polycystic kidney disease family with misleading linkage analysis data

• Entezam M
• Khatami MR
• Saddadi F
• Ayati M
• Roozbeh J
• Keramatipour M

• KMID: 2311829
• DOI: http://doi.org/10.1016/j.krcp.2016.02.003

Abstract

BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disorder caused by mutation in 2 genes PKD1 and PKD2. Thus far, no mutation is identified in approximately 10% of ADPKD families, which can suggest further locus heterogeneity. Owing to the complexity of direct mutation detection, linkage analysis can initially identify the responsible gene in appropriate affected families. Here, we evaluated an Iranian ADPKD family apparently unlinked to both PKD1 and PKD2 genes. This is one of the pioneer studies in genetic analysis of ADPKD in Iranian population.
METHODS
Linkage reanalysis was performed by regenotyping of flanking microsatellite markers in 8 individuals of the ADPKD family. Direct mutation analysis was performed by Sanger sequencing.
RESULTS
Mutation analysis revealed a pathogenic mutation (c.1094+1G>A) in the PKD2 gene in the proband. Analyzing 2 healthy and 4 clinically affected members confirmed the correct segregation of the mutation within the family and also ruled out the disease in 1 suspected individual. Misinterpretation of the linkage data was due to the occurrence of 1 crossing over between the PKD2 intragenic and the nearest downstream marker (D4S2929). Homozygosity of upstream markers caused the recombination indistinguishable.
CONCLUSION
Although analysis of additive informative polymorphic markers can overcome the misleading haplotype data, it is limited because of the lack of other highly polymorphic microsatellite markers closer to the gene. Direct mutation screening can identify the causative mutation in the apparently unlinked pedigree; moreover, it is the only approach to achieve the confirmed diagnosis in individuals with equivocal imaging results.

Keyword

Autosomal dominant polycystic kidney disease; Linkage analysis; Mutation screening; Recombination

MeSH Terms

Crossing Over, Genetic
Diagnosis
Haplotypes
Humans
Mass Screening
Microsatellite Repeats
Pedigree
Polycystic Kidney, Autosomal Dominant*
Population Characteristics
Recombination, Genetic