The Importance of Familial Co‐segregation in the Classification of a Novel PKD1 Variant Associated With Autosomal Dominant Polycystic Kidney Disease

{"Autosomal":[0],"dominant":[1],"polycystic":[2],"kidney":[3,21],"disease":[4],"(ADPKD)":[5],"is":[6,80,180,209],"a":[7,62,68,224],"highly":[8],"penetrant":[9],"and":[10,67,90,97,107,118,136,148,172,186,202,215,236],"clinically":[11,210],"recognizable":[12],"disorder,":[13],"characterized":[14],"by":[15,42],"the":[16,25,36,50,114,119,128,190,204,228,231],"presence":[17],"of":[18,33,52,146,212,227,233],"multiple":[19,77],"bilateral":[20],"cysts.":[22],"Variants":[23,110],"in":[24,44,168,174,219,240],"PKD1":[26,70,162],"or":[27,40,92],"PKD2":[28],"genes":[29],"cause":[30],"approximately":[31],"90%":[32],"cases,":[34],"with":[35,64,76,127,198],"remaining":[37],"10%":[38],"unresolved":[39],"caused":[41],"variants":[43],"other":[45],"loci.":[46],"This":[47,195,207],"study":[48],"demonstrates":[49],"utility":[51],"segregation":[53,234],"studies":[54,235],"for":[55],"classifying":[56],"genetic":[57,152,241],"variants,":[58],"as":[59,192],"applied":[60],"to":[61,184],"family":[63,75,138,208],"severe":[65],"ADPKD":[66,78,214],"novel":[69],"missense":[71],"variant.":[72],"A":[73],"large":[74],"patients":[79,171],"described.":[81],"Genetic":[82],"testing":[83,153],"was":[84,125,155,166],"performed":[85],"using":[86,103,113],"Sanger":[87],"sequencing":[88],"(PKD1":[89],"PKD2)":[91],"NGS":[93],"panel":[94],"(PKD1,":[95,105],"PKD2,":[96,106],"PKHD1":[98,108],"genes).":[99,109],"CNV":[100],"were":[101,111],"excluded":[102,173],"MLPA":[104],"classified":[112],"2015":[115],"ACMG-AMP":[116],"guidelines,":[117],"full":[120],"likelihood":[121],"Bayes":[122],"factor":[123],"(FLB)":[124],"computed":[126],"\\"segregatr\\"":[129],"R-package":[130],"(Version":[131],"0.3.0).":[132],"The":[133,160,178],"index":[134],"patient":[135],"13":[137],"members":[139],"across":[140],"three":[141],"generations":[142],"had":[143],"ultrasonographic":[144],"confirmation":[145],"typical":[147],"progressive":[149],"ADPKD.":[150],"Preimplantation":[151],"(PGT)":[154],"requested,":[156],"requiring":[157],"molecular":[158],"confirmation.":[159],"heterozygous":[161],"VUS":[163,218],"c.8999G>C":[164],"p.(Arg3000Pro)":[165],"identified":[167],"four":[169],"affected":[170],"one":[175,217],"unaffected":[176],"patient.":[177],"FLB":[179,221],"96.8,":[181],"which,":[182],"according":[183],"Jarvik":[185],"Browning's":[187],"criteria,":[188],"reclassified":[189],"variant":[191,242],"likely":[193],"pathogenic.":[194],"classification":[196],"aligned":[197],"ClinGen's":[199],"2024":[200],"recommendations":[201],"justified":[203],"PGT":[205],"request.":[206],"suggestive":[211],"PKD1-related":[213],"shares":[216],"PKD1.":[220],"calculation":[222],"enabled":[223],"rapid":[225],"reclassification":[226],"variant,":[229],"demonstrating":[230],"value":[232],"accurate":[237],"clinical":[238],"phenotyping":[239],"annotation.":[243]}

Authors

Institutions

Publication Details

Journal
American Journal of Medical Genetics Part A
Published
2026-09-06
DOI
https://doi.org/10.1002/ajmg.a.70298
Primary Topic
Genetic and Kidney Cyst Diseases
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
article

The Importance of Familial Co‐segregation in the Classification of a Novel PKD1 Variant Associated With Autosomal Dominant Polycystic Kidney Disease

João Paulo Oliveira, Susana Fernandes, A Vasconcelos, Liliana Rocha
American Journal of Medical Genetics Part A
Genetic and Kidney Cyst Diseases
article

The Importance of Familial Co‐segregation in the Classification of a Novel PKD1 Variant Associated With Autosomal Dominant Polycystic Kidney Disease

João Paulo Oliveira, Susana Fernandes, A Vasconcelos, Liliana Rocha
article en

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a highly penetrant and clinically recognizable disorder, characterized by the presence of multiple bilateral kidney cysts. Variants in the PKD1 or PKD2 genes cause approximately 90% of cases, with the remaining 10% unresolved or caused by variants in other loci. This study demonstrates the utility of segregation studies for classifying genetic variants, as applied to a family with severe ADPKD and a novel PKD1 missense variant. A large family with multiple ADPKD patients is described. Genetic testing was performed using Sanger sequencing (PKD1 and PKD2) or NGS panel (PKD1, PKD2, and PKHD1 genes). CNV were excluded using MLPA (PKD1, PKD2, and PKHD1 genes). Variants were classified using the 2015 ACMG-AMP guidelines, and the full likelihood Bayes factor (FLB) was computed with the "segregatr" R-package (Version 0.3.0). The index patient and 13 family members across three generations had ultrasonographic confirmation of typical and progressive ADPKD. Preimplantation genetic testing (PGT) was requested, requiring molecular confirmation. The heterozygous PKD1 VUS c.8999G>C p.(Arg3000Pro) was identified in four affected patients and excluded in one unaffected patient. The FLB is 96.8, which, according to Jarvik and Browning's criteria, reclassified the variant as likely pathogenic. This classification aligned with ClinGen's 2024 recommendations and justified the PGT request. This family is clinically suggestive of PKD1-related ADPKD and shares one VUS in PKD1. FLB calculation enabled a rapid reclassification of the variant, demonstrating the value of segregation studies and accurate clinical phenotyping in genetic variant annotation.

American Journal of Medical Genetics Part A
Universidade do Porto (PT), Hospital de São João (PT), i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT)
Good health and well-being
Openalex Percentile: Top 11%
Genetic and Kidney Cyst Diseases
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.