Genetic diagnosis in consanguineous families with kidney disease by homozygosity mapping coupled with whole-exome sequencing

Background: Accurate diagnosis of the primary cause of an individual's kidney disease can be essential for proper management. Some kidney diseases have overlapping histopathologic features despite being caused by defects in different genes. In this report, we describe 2 consanguineous Saudi Arabian families in which individuals presented with kidney failure and mixed clinical and histologic features initially believed to be consistent with focal segmental glomerulosclerosis.

Study design: Case series.

Setting & participants: We studied members of 2 apparently unrelated families from Saudi Arabia with kidney disease.

Measurements: Whole-genome single-nucleotide polymorphism analysis followed by targeted isolation and sequencing of exons using genomic DNA samples from affected members of these families, followed by additional focused genotyping and sequence analysis.

Results: The 2 apparently unrelated families shared a region of homozygosity on chromosome 2q13. Exome sequence from affected individuals lacked sequence reads from the NPHP1 gene, which is located within this homozygous region. Additional polymerase chain reaction-based genotyping confirmed that affected individuals had NPHP1 deletions, rather than defects in a known focal segmental glomerulosclerosis-associated gene.

Limitations: The methods used here may not result in a clear genetic diagnosis in many cases of apparent familial kidney disease.

Conclusions: This analysis shows the power of new high-throughput genotyping and sequencing technologies to aid in the rapid genetic diagnosis of individuals with an inherited form of kidney disease. We believe it is likely that such tools may become useful clinical genetic tools and alter the manner in which diagnoses are made in nephrology.