Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases
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BRIEF REVIEW www.jasn.org Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases Emilie Cornec-Le Gall,1,2 Vicente E. Torres,1 and Peter C. Harris1 1Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; and 2Department of Nephrology, University Hospital, European University of Brittany, and National Institute of Health and Medical Sciences, INSERM U1078, Brest, France ABSTRACT Data indicate significant phenotypic and genotypic overlap, plus a common patho- ADPLD (Table 1).15–20 The difference in genesis, between two groups of inherited disorders, autosomal dominant polycystic renal survival between PKD1 and PKD2 kidney diseases (ADPKD), a significant cause of ESRD, and autosomal dominant patients has been highlighted in multiple polycystic liver diseases (ADPLD), which result in significant PLD with minimal studies (Table 2).3,21 In addition, PKD1 PKD. Eight genes have been associated with ADPKD (PKD1 and PKD2), ADPLD patients have a larger height-adjusted total (PRKCSH, SEC63, LRP5, ALG8,andSEC61B), or both (GANAB). Although genetics kidney volume (HtTKV; an early measure is only infrequently used for diagnosing these diseases and prognosing the associ- of the severity of renal disease in ADPKD) ated outcomes, its value is beginning to be appreciated, and the genomics revolu- and lower eGFR than PKD2 patients.14,22 tion promises more reliable and less expensive molecular diagnostic tools for these A further difference is the number of kid- diseases. We therefore propose categorization of patients with a phenotypic and ney cysts, with fewer in PKD2 than PKD1 genotypic descriptor that will clarify etiology, provide prognostic information, and (Figure 1, A and C), although the rate of better describe atypical cases. In genetically defined cases, the designation would growth of the kidneys does not differ be- include the disease and gene names, with allelic (truncating/nontruncating) infor- tween the groups.23 Occasionally, severe mation included for PKD1. Recent data have shown that biallelic disease including at PLD can be the major clinical phenotype least one weak ADPKD allele is a significant cause of symptomatic, very early onset in ADPKD (Figure 1, B and G). PRKCSH ADPKD. Including a genic (and allelic) descriptor with the disease name will provide and SEC63 have not been clinically dif- outcome clues, guide treatment, and aid prevalence estimates. ferentiated and majorly consist of PLD without renal cysts, although a few kid- J Am Soc Nephrol 29: 13–23, 2018. doi: https://doi.org/10.1681/ASN.2017050483 ney cysts have been described in 28%– 35% of cases, and renal involvement may have been underestimated (Figure CLINICAL AND GENETIC liver disease (ADPLD) is characterized as 1H).9 Missense mutations to LRP5 have CHARACTERISTICS OF ADPKD PLD, including severe, symptomatic dis- been identified in four families, two with AND ADPLD ease that is indistinguishable from that moderate-to-severe PLD without renal found in ADPKD, but without (or only oc- cysts, one with moderate PLD and three Disease severity in autosomal dominant casional) renal cysts.9 kidney cysts, and one with mild PLD but polycystic kidney disease (ADPKD) is ADPKD is genetically heterogeneous, severe PKD in one family member.19 The 1 PKD1 highly variable. Whereas half of affected with two major genes, (Chr. 16.p13.3; renal prognosis in GANAB is consistently PKD2 individuals reach ESRD by approximately approximately 78% families) and mild with progression to ESRD unlikely 60 years,2,3 ,1% of patients exhibit very (4p21; approximately 15%), and a rare third early onset (VEO) disease, with a diagnosis locus, GANAB (11q12.3; approximately made in utero or during infancy.4–6 At the 0.3%), discovered last year.3,10–15 For PRKCSH Published online ahead of print. Publication date other end of the spectrum, patients can ADPLD, (19p13.2; approximately available at www.jasn.org. live a normal lifespan without requiring 20%) and SEC63 (6q21; approximately RRT. Most patients with ADPKD develop 15%) are the major genes, but LRP5 Correspondence: Dr. Peter C. Harris, Division of GANAB Nephrology and Hypertension, Mayo Clinic, 200 liver cysts as they age, with severe Polycystic (11q13.2), (approximately 2%), First Street, SW, Rochester, MN 55905. Email: harris. liver disease (PLD) requiring surgical inter- ALG8 (11q14.1; approximately 3%), and [email protected] SEC61B vention occurring in a small minority of (9q22.33; approximately 1%) Copyright © 2018 by the American Society of patients.7,8 Autosomal dominant polycystic have more recently been associated with Nephrology J Am Soc Nephrol 29: 13–23, 2018 ISSN : 1046-6673/2901-13 13 BRIEF REVIEW www.jasn.org Table 1. Classification of ADPKD and ADPLD including gene descriptor Phenotype Designationa Description Example PKD ESRD Risk (Age) PLD ADPKDb ADPKD-PKD1T ADPKD due to PKD1 Severe Very high (55 yr) Absent to severe Figure 1A, Table 2 truncating mutationc ADPKD-PKD1NT ADPKD due to PKD1 Mild to severe High (67 yr) Absent to severe Figure 1, B and G, Table 2 nontruncating mutationd ADPKD-PKD1 ULP ADPKD due to PKD1 ultra Extremely mild None Absent to severe Figure 1D, Table 4 low penetrance allele ADPKD-PKD2 ADPKD due to PKD2 mutation Mild Low (79 yr) Absent to severe Figure 1C, Table 2 ADPKD-GANAB ADPKD due to GANAB mutation Very mild None Absent to severe Figure 1E, Table 2 ADPLDe ADPLD-PRKCSH ADPKD due to PRKCSH mutation Absent to very mild None Mild to severe Figure 1H ADPLD-SEC63 ADPKD due to SEC63 mutation Absent to very mild None Mild to severe 18 ADPLD-LRP5 ADPKD due to LRP5 mutation Absent to very mild None Mild to severe 19 ADPLD-GANAB ADPLD due to GANAB mutation Very mild None Mild to severe Table 2 ADPLD-ALG8 ADPLD due to ALG8 mutation Absent to very mild None Absent to severe 20 ADPLD-SEC61B ADPLD due to SEC61B mutation Absent to very mild None Mild to severe 20 Biallelicf ADPKD-PKD1a,b Typical ADPKD due to Severe High to very high Absent to severe Table 4 two PKD1 alleles a,b ADPKDVEO-PKD1 Symptomatic infantile ADPKD Severe infantile Extremely high Absent to mild Table 4 due two PKD1 alleles a,b ADPKDVEO-PKD2 Symptomatic infantile ADPKD Severe infantile Extremely high Absent to mild Table 4 due two PKD2 alleles T, truncating; NT, nontruncating. aExamples are shown to illustrate the disease plus gene terminology but other combinations are possible. bADPKD is defined as dominantly inherited disease with significant PKD,31,32 with or without significant PLD, and without phenotypes suggesting an alternative disease. Subjects with a proven pathogenic ADPKD allele, even if the renal disease does reach the imaging criteria, would be considered ADPKD. cFrameshifting deletion, duplication or insertion, nonsense, typical splicing mutation (disrupting the canonic intronic dinucleotides), or inframe deletion, dupli- cation or insertion of $5 amino acids. dMissense, atypic splicing mutation (not disrupting the canonic intronic dinucleotides), or inframe deletion, duplication, or insertion of #4 amino acids. eADPLD is defined as dominantly inherited disease with significant PLD without significant PKD. fPKD due to two mutations to the same ADPKD gene found on opposite alleles (in trans). (Figure 1E), although all patients had in the kidney, which can largely be res- workup or the therapeutic decision- some kidney cysts; predominant liver cued by Pkd1 overexpression.26 The ac- making algorithms of several kidney dis- involvement was described in 4 of 11 tion of these genes, and of GANAB, eases, including steroid-resistant FSGS, families.15,20 Inactivating mutations to ALG8,andSEC61B, seems to be through atypichemolyticuremicsyndrome,and ALG8 were recently shown to cause inefficient maturation and trafficking of Alport syndrome.30 The introduction of ADPLD in five pedigrees, four with se- membrane/secreted proteins, with the next-generation sequencing (NGS) has vere PLD and some kidney cysts, but one PKD1 protein, polycystin-1 (PC1), par- allowed the development of cost- and patient only had renal cysts.20 Mutations ticularly susceptible to dosage reduction time-efficient strategies, often including to SEC61B were identified in two fami- of any of these proteins.15,20,26,27 screening panels of candidate genes or lies with mild PLD and no apparent re- whole-exome sequencing, improving nal phenotype.20 diagnostics, providing prognostic value, A loss-of-function genetic mechanism AN INCREASING ROLE FOR and broadening the phenotypic spec- (due to a dosage/threshold or somatic sec- ROUTINE GENETIC ANALYSIS IN trum of many kidney diseases.30 ond hit mechanism) has been established ADPKD AND ADPLD? Genetics is presently rarely used for for these diseases.24 Studies of pathogenesis routine diagnostics and prognostics in of ADPKD and ADPLD also show a com- Molecular genetics has been performed ADPKD and ADPLD, with imaging monality with all ADPLD proteins (except routinely for several years in the manage- much more commonly employed for LRP5) involved in the glycosylation, quality mentofanumberofmonogenicdisorders, these purposes.22,31–34 However, because control assessment, or translocation across such as cystic fibrosis, where it is used new methods are revolutionizing molec- the ER membrane of membrane/secreted for diagnostics and also recently to guide ular diagnostics, increasing availability, proteins.15,20,25 A renal cystic phenotype is allelic-specific therapeutics.28,29 Genetic and reducing costs35—and the prognostic induced by inactivation of Prkcsh or Sec63 testing is part of either the diagnosis value