Cutting-edge genetic tools diagnosed 83% of Irish patients with polycystic kidney disease (PKD), identified 36 novel variants, and discovered that seemingly unrelated individuals with the same variant likely inherited it from a common ancestor.
A study conducted in Ireland in patients with polycystic kidney disease (PKD) found that a combination of cutting-edge molecular genetic tools diagnosed 83% of Irish patients known to have the disease, discovered 36 novel variants, and found that seemingly unrelated individuals carrying the same variant probably inherited it from a common ancestor.
PKD is an inherited disorder that causes of clusters of cysts to develop, resulting in enlarged kidneys and loss of function. PKDs are not only the leading cause of inherited renal disease overall in the world, affecting an estimated 12.5 million individuals, but a leading cause of end-stage kidney disease (ESKD).
In a study published earlier this year in the European Journal of Human Genetics, researchers recruited a cohort of 169 Irish PKD patients to explore the genetic variations of the population, one that is conducive to study due to its relative homogeneity. Focus largely was on autosomal dominant disease (ADPKD), with previous research showing that 85% of patients reach ESKD by age 65, although those with the rarer autosomal recessive disease (ARPKD) also were studied.
Researchers used a combination of molecular genetic tools to achieve an 83% diagnostic rate (141 patients). They succeeded in diagnosing 91% of the 141 patients using next generation sequencing (NGS) alone but needed to use long-range polymerase chain reaction (LR-PCR) and Sanger sequencing approaches for the others. LR-PCR and Sanger sequencing remain the gold standard, the authors wrote, but NGS is establishing its utility as an automated method that can perform a high volume of tests in a short time.
Two-thirds of the patients (113) were identified an AD pathogenic variant in PKD1, which has a high GC-content and is in a segmentally duplicated part of the genome with 6 pseudogenes, making it challenging to identify. The study confirmed earlier research showing that patients with AD pathogenic genetic variants tend to reach ESKD at an earlier age than those with PKD2. Those with PKD1 in the study were estimated to reach ESKD at age 50, and those with PKD2 at 70.
The researchers also identified 14 AD pathogenic variants in PKD1 and PKD2 in multiple unrelated patients. The most likely reason would be that the patients are distant relatives and the variants come from a common ancestor, the researchers wrote.
The study also compared the standard Mayo Clinic variant classification guidelines against those published the American College of Medical Genetics and Genomics (ACMG), which have been embraced by the scientific community but not gained traction among researchers for regular use. The ACMG guidelines were less effective in diagnosis, with only a 71% diagnostic rate compared to 83% for Mayo, according to the study.
Among the weaknesses, the authors said, is that ACMG is better for pediatric-onset rare diseases, not adult. They noted that ACMG guidelines were developed for clinical use, while those for Mayo were designed for research only.
However, using those guidelines did result in identifying 36 novel, likely disease-causing variants.
Benson KA, Murray SL, Senum SR, et al. The genetic landscape of polycystic kidney disease in Ireland. Eur J Hum Genet (2021). Published online January 16, 2021. doi: 10.1038/s41431-020-00806-5