{"doi":"10.1016/j.ekir.2020.05.008","title":"Reconsidering Genetic Testing for Neonatal Polycystic Kidney Disease","abstract":"Polycystic kidney disease (PKD) is a condition typified by numerous renal cysts and enlarged kidneys. Types of PKD are generally distinguished by the genetic mode of inheritance, either autosomal dominant (ADPKD) or autosomal recessive (ARPKD). In addition, ADPKD and ARPKD are characterized by differences in clinical and pathological presentations. Whereas ADPKD presents with bilateral renal enlargement and macrocysts, extrarenal cysts (hepatic), intracranial aneurysms, mitral valve prolapse, and a biphasic pattern of progression to end-stage renal disease (ESRD) in later decades of life, ARPKD is characterized by early and rapid enlargement of the kidneys, childhood progression to ESRD, and frequent liver involvement leading to congenital hepatic fibrosis. Because of these differences, family history and clinical presentation are the primary factors used to direct the genetic testing ordered to establish a molecular diagnosis. When a family history includes suspected ADPKD affecting individuals in 1 or more generations, sequencing and/or deletion/duplication analysis of PKD1 and PKD2 is considered. When a family history includes a child with either prenatal or early pediatric onset of PKD, sequencing and/or deletion/duplication analysis of PKHD1 is pursued. Although pathogenic variants in PKD1 and PKD2 account for nearly all PKD cases that appear to be AD, pathogenic variants detected in PKHD1 account for only ∼75% of PKD cases that appear to be AR.1Melchionda S. Palladino T. Castellana S. et al.Expanding the mutation spectrum in 130 probands with ARPKD: identification of 62 novel PKHD1 mutations by Sanger sequencing and MLPA analysis.J Hum Genet. 2016; 61: 811-821Crossref PubMed Scopus (12) Google Scholar Historically, it has been unclear whether these ostensibly AR cases of PKD without detected PKHD1 pathogenic variants represent atypical early manifestations of ADPKD or whether there are yet-unknown genes responsible for an early-onset AR presentation of PKD. Although this landscape is rapidly changing with increasing use of massively parallel sequencing in the form of either gene panels or exome sequencing, particularly in a research setting, clinical practice has been slow to change—although many providers now offer gene panels for evaluation, particularly in the neonatal setting. Research to further understand this phenomenon has yielded important information about the mechanism of disease in PKD. Historically, a “2-hit” hypothesis was supported based on the combination of germline and somatic mutations seen in cysts and the severe, lethal phenotype of homozygous knockout Pkd1 mice.2Reeders S.T. Multilocus polycystic disease.Nat Genet. 1992; 1: 235-237Crossref PubMed Scopus (80) Google Scholar, 3Lu W. Peissel B. Babakhanlou H. et al.Perinatal lethality with kidney and pancreas defects in mice targeted PKD1 mutation.Nat Genet. 1997; 17: 179-181Crossref PubMed Scopus (361) Google Scholar, 4Pei Y. Watnick T. He N. et al.Somatic PKD2 mutations in individual kidney and liver cysts support a ‘two-hit’ model of cystogenesis in type 2 autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 1999; 10: 1524-1529Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar However, further research in mice with reduced Pkd1 expression has established a dose-dependent model of disease, suggesting that modifier alleles may contribute to the severity and onset of cyst development.5Lantinga-van Leeuwen I.S. Dauwerse J.G. Baelde H.J. et al.Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease.Hum Mol Genet. 2004; 13: 3069-3077Crossref PubMed Scopus (236) Google Scholar,6Hopp K. Ward C.J. Hommerding C.J. et al.Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity.J Clin Invest. 2012; 122: 4257-4273Crossref PubMed Scopus (194) Google Scholar Multiple studies of families with ADPKD have implicated variants in PKD1, PKD2, PKHD1, or HNF1B inherited in trans with known ","journal":"Kidney International Reports","year":2020,"id":111067,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.967,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":282701,"name":"Monica H. Wojcik","orcid":"0000-0002-8162-5031","position":1,"is_corresponding":false},{"id":308542,"name":"Casie A. Genetti","orcid":"0000-0003-4173-9947","position":2,"is_corresponding":false},{"id":437124,"name":"Thomas E. Mullen","orcid":null,"position":3,"is_corresponding":false},{"id":308547,"name":"Pankaj B. Agrawal","orcid":"0000-0003-3255-0456","position":4,"is_corresponding":false},{"id":398449,"name":"Deborah R. Stein","orcid":null,"position":5,"is_corresponding":false},{"id":322767,"name":"Grace E. VanNoy","orcid":"0000-0003-1257-9702","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-18T23:13:01.914939Z","pmid":"32775833","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}