PKD2 founder mutation is the most common mutation of polycystic kidney disease in Taiwan

Abstract

Autosomal Dominant polycystic kidney disease (ADPKD) is the most common inherited adult kidney disease. Although ADPKD is primarily caused by PKD1 and PKD2, the identification of several novel causative genes in recent years has revealed more complex genetic heterogeneity than previously thought. To study the disease-causing mutations of ADPKD, a total of 920 families were collected and their diagnoses were established via clinical and image studies by Taiwan PKD Consortium investigators. Amplicon-based library preparation with next-generation sequencing, variant calling, and bioinformatic analysis was used to identify disease-causing mutations in the cohort. Microsatellite analysis along with genotyping and haplotype analysis was performed in the PKD2 p.Arg803* family members. The age of mutation was calculated to estimate the time at which the mutation occurred or the founder arrived in Taiwan. Disease-causing mutations were identified in 634 families (68.9%) by detection of 364 PKD1, 239 PKD2, 18 PKHD1, 7 GANAB, and 6 ALG8 pathogenic variants. 162 families (17.6%) had likely causative but non-diagnostic variants of unknown significance (VUS). A single PKD2 p.Arg803* mutation was found in 17.8% (164/920) of the cohort in Taiwan. Microsatellite and array analysis showed that 80% of the PKD2 p.Arg803* families shared the same haplotype in a 250 kb region, indicating those families may originate from a common ancestor 300 years ago. Our findings provide a mutation landscape as well as evidence that a founder effect exists and has contributed to a major percentage of the ADPKD population in Taiwan.

Fig. 1. Mutation Profile of Taiwan ADPKD cohort.

a 920 ADPKD families were analyzed by next-generation sequencing-based PKD panel. Disease-causing mutations were identified in 634 families (68.9%) by detection 364 PKD1, 239 PKD2, 18 PKHD1, 7 GANAB, and 6 ALG8 pathogenic variants. 162 families (17.6%) had likely causative but non-diagnostic variants of unknown significance (VUS). No class 3–5 ACMG variants were identified in the remaining 124 families. b Missense, frameshift indel, and truncating mutations were the most common changes in PKD1-associated families. c The p.Arg803* represented 61% of PKD2 changes. Missense and splicing site variants were the most common changes in PKD2-associated families if p.Arg803* was not included. LP likely pathogenic, P pathogenic, VUS variant of unknown significance.

Fig. 2. Variants distribution of PKD1 and PKD2 genes.

Variants in the PKD1 and PKD2 distributed evenly across genes with no single variant exceeded 1.2% of the cohort if the PKD2 p.Arg803* variant was excluded. Figures were created and modified by using the MutationMapper.

Fig. 3. Geographic location, percentage, age of mutation, and principle component analysis of PKD2 p.Arg803*.

a Geographically, PKD2 p.Arg803* was found all over Taiwan and represented 10–25% of the ADPKD collected from different area. Extreme PKD2 p.Arg803* percentages (0 and 50%) were most likely due to small sampling sizes. The number represented PKD2 p.Arg803* family identified in that county along with its percentage (in brackets). b The histogram produced by the DMLE + 2.3 showed the posterior probability plot of the estimated mutation age of the 250 kb region of PKD2 p.Arg803*. With average population growth rate of 1.31%, the estimated peak age appeared 12.6 generations ago (95% CI: 9.4–16.0). Assuming 25 years as an average generation, the PKD2 p.Arg803* mutation was introduced 300 years ago (95% CI: 235–398, indicated by the gray bar) in Taiwan. c The principal component analysis of genetic structure across 96 PKD2 p.R803* carriers, 480 control individuals from Taiwan Biobank, and HapMap Project. ASW African ancestry in Southwest USA, CEU Utah residents with Northern and Western European ancestry from the CEPH collection, CHB Han Chinese in Beijing, China, CHD Chinese in Metropolitan Denver, Colorado, CI confidence interval, GIH Gujarati Indians in Houston, Texas, JPT Japanese in Tokyo, Japan, LWK Luhya in Webuye, Kenya, MXL Mexican ancestry in Los Angeles, California, MKK Maasai in Kinyawa, Kenya, TWB Taiwan Biobank, TSI Toscani in Italia, YRI Yoruba in Ibadan, Nigeria.

Fig. 4. Genetic recombination of the PKD2 region in family DY1466.

a In family DY1466 with 6 PKD2 R803* affected individuals, members III-1 and III-2 were found to carry different microsatellite markers and haplotypes. They had only 72 kb (10 SNPs) within this 250 kb region that was the same as their father. b Although II-1 and II-2 carried the common R803* haplotype along with the D4S1563 marker, gene recombination most likely occurred in individual II-1, with a 72 kb allele crossover leading to both of his children having the PKD2 p.R803* mutation but different haplotypes.

Fig. 5. Exemplary imaging in atypical cases of ADPKD.

Genotypes and phenotypes of families with atypical APDKD. a Family DY2242: ALG8 c.175-2A>G variant. Abdominal CT showing bilateral polycystic kidney disease with liver cysts at the age of 44. b Family DY1920: ALG8 p.Gly275fs variant. Abdominal CT shows bilateral polycystic kidney disease without liver cyst at the age of 65. The index case and the daughter (II-1) also have a pathogenic SPAST p.Gly382Cys which is compatible with their clinical features of spastic paraplegia. c Family DY1591: GANAB p.Val4_Ala5del variant. Renal ultrasound shows bilateral multiple kidney cysts with preserved kidney contour at the age of 38. d Family DY778: GANAB p.Arg443* variant. Abdominal CT shows bilateral multiple kidney cysts and hematoma in right kidney due to right renal artery pseudoaneurysm rupture at the age of 48. The patient received continuous ambulatory peritoneal dialysis at the age of 47. Patients’ clinical status at the time of images are illustrated by filled black symbols (ESKD) and gray symbols (CKD stage 1–3). e Family DY95: compound heterozygous PKD1 variants (p.Cys259Tyr/p.Ala1458fs). Abdominal computed tomography (CT) shows liver cysts and bilateral polycystic kidney disease at the age of 33 in II-4, and only a total of 4 cysts (2 on each kidney, CT showing cysts in the left kidney) at the age of 71 in the father (I-1). No kidney cyst was detected in the sister II-2 at the age of 40. Both I-1 and II-2 have eGFR > 60 ml/min/1.72 M² and 100 ml/min/1.72 M² at the time of CT survey, respectively. f Family DY2061: compound heterozygous PKD1 variants (p.Arg4150Cys/p.Thr3539Ile). Renal ultrasound shows enlarged kidneys of more than 15 cm with bilateral multiple kidney cysts at the age of 29. g Family DY2184: p.Arg375Gln. Index case II-1 had a total of three cysts (one in the right kidney and 2 in the left kidney) at the age of 25, however, the mother (I-2) has only one cyst at the age of 55.