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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 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 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

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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 is starting to be realized36—we

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Table 2. Age at ESRD in the different ADPKD subgroups Disease Number of Patients (Number of Pedigrees) Median Age at ESRD, yr Reference, Year of Publication ADPKD-PKD1T 219 (54) 54 59, 2002 701 (450) 55.1 36, 2016 249 (72) 52.5 55, 2016 ADPKD-PKD1NT 323 (228) 65.8 36, 2016 152 (51) 70.8a 55, 2016 ADPKD-PKD2 291 (31) 74 21, 1999 395 (71) 72 85, 2003 117 (23) 70 101, 2009 248 (172) 77.8 36, 2016 213 (57) 80 55, 2016 293 (203) 77.8 97, 2017 ADPKD-GANAB 22 (11) No cases of ESRD described 15, 2016 20, 2017 aTGESP PKD1NT group included nonsynonymous missense mutations but excluded patients with inframe short deletion or insertion. propose that genetic information can play a However, the consequences of employing capture methods and diversity in the more central role in the management of such a patient as a kidney donor in terms groups offering clinical ADPKD molecu- patients with ADPKD and ADPLD. of their long-term renal function is un- lar diagnostics is likely to increase its avail- known; these patients can have clinically ability and reduce costs, even if specificity significant extrarenal complications and sensitivity data are not yet widely THE DIAGNOSIS VALUE OF themselves or in offspring, such as PLD available.52,53 Second, although both dis- MOLECULAR GENETICS IN ADPKD in GANAB,15,20 and evidence that biallelic eases are genetically heterogeneous (Table disease, the coincidence of a ULP PKD1 1), because the majority of clinically sig- Simple renal cysts (not considered to be allele in trans with a fully inactivating nificant renal patients are PKD1 the value of germline genetic origin) are com- PKD1 allele, can result in early onset PKD of testing is perceived as limited. However, monly observed in the general popula- (see later section), suggests that obtaining a evidence of the incomplete penetrance of tion and increase in frequency with firm diagnosis is important.4,41–45 many nontruncating PKD1 alleles (not age.37,38 Consequently, age-related cyst fully inactivating the protein and so asso- number criteria have been determined ciated with milder kidney disease, also for ultrasound (U/S), or the more sensi- GENETIC DIAGNOSTICS IN ADPKD termed hypomorphic) has shown poten- tive MRI, to diagnose ADPKD, or to AND ADPLD: PROGNOSTICS, tial prognostic value, and is changing this exclude a diagnosis in the setting of a COMPLICATIONS, AND perception.3,14,41,54,55 Third, there is ex- positive family history.31,32 As an exam- PROSPECTS treme allelic heterogeneity, with .1500 ple, .10 total cysts detected by MRI are different PKD1, .250 PKD2, .30 considered sufficient for a positive diag- Genetic testing in the clinical management PRKCSH,and.35 SEC63 pathogenic nosis in subjects ,40 years. These crite- of these diseases has been overlooked for mutations described (with fewer for the ria work well in the setting of a positive several reasons. First, analysis of PKD1 has other genes), necessitating analysis of the family history if multiple bilateral cysts been complicated due to its location in a coding regions of all genes for compre- (.10 per kidney) are detected, or if no segmentally duplicated region of the ge- hensive analysis.9,20,56 Sanger-based single cysts are detected in an older individual. nome; three-quarters of the gene, 59 to gene approaches were hence costly and However, if the family history is negative exon 1 to exon 33, is duplicated six times cumbersome, but with NGS panel ap- (10%–25% of ADPKD families39,40) more proximally on 16, proaches simultaneous screening of all and/or when few cysts are detected, the where they encode pseudogenes with genes is possible. Fourth, because 30%– imaging-based diagnosis is less clear. This high sequence similarity to PKD1.10,46,47 35% of PKD1 pathogenic alleles are non- uncertainty is exemplified by GANAB, or Hence, long-range PCR methods have truncating (with significant levels at the patients with ADPKD due to an ultra-low been employed to specifically amplify other loci), it has proved a challenge to dif- penetrant (ULP) PKD1 allele (Figure 1, D PKD1 for molecular diagnostics by Sanger ferentiate pathogenic from neutral changes, and E), where only a small number (or even or NGS, with doubts that this gene is ade- and their degree of penetrance.3,14 The no) cysts might be detected, although ge- quately covered by whole-exome sequenc- development of better algorithms for netically they are proven affected.15,41,42 It ing methods, limiting the availability and predicting the pathogenicity and pene- might be considered unimportant to di- increasing the costs of testing.39,48–51 How- trance of nontruncating gene variants, agnose these individuals because they are ever, the development of specificNGSpro- collation of information on these vari- unlikely to develop renal insufficiency. tocols to screen PKD1 by hybridization ants (pathogenic to neutral), and more

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informative diagnostic reports will in- crease the value of molecular diagnostics in these disorders.14,56,57

INTRODUCING A DISEASE, PLUS GENE AND ALLELIC TERMINOLOGY FOR ADPKD AND ADPLD

In autosomal dominant tubulointerstitial kidney disease (ADTKD), where there is also genetic and phenotypic heterogeneity, a terminology describing the disease and the genetic etiology has been adopted (i.e., ADTKD-MUC1, ADTKD-UMOD, ADTKD-HNF1B, and ADTKD-REN).58 We propose to introduce a similar nosol- ogy for ADPKD/ADPLD (see Table 1 for

that a few large cysts in the right kidney largely explain the enlarged HtTKV. (D) ADPKD-PKD1 ULP: Contrast-enhanced CT- scan of a 48-year-old woman, with a ULP PKD1 nontruncating mutation (c.9829C.T, p.Arg3277Cys), who has a total of five cysts in the right kidney and one cyst in the left kidney, a normal eGFR, and nonenlarged kidneys. (E) ADPKD-GANAB: CT-scan of 45-year-old woman with a GANAB muta- tion (c.1914_1915delAG; p.Asp640fs) who has bilateral kidney cysts, a normal eGFR (104 ml/min) and HtTKV (318 ml/m), and without significant PLD. (F) A common dif- ferential diagnosis: ADTKD:HNF1B.MRIof 30-year-old woman with a large deletion of the entire HNF1B gene, who has preserved kidney function (75.5 ml/min per 1.73 m2) and approximately ten cysts per kidney (HtTKV=196.9 ml/m). (G) ADPKD-PKD1NT MRI of 54-year-old woman with severe PLD (HtTLV=4695 ml/min; liver resection per- formed after this MRI) and normal-sized kid- neys, with a total of 12 bilateral small cysts. A PKD1NT allele was identified (c.3284A.G, p.Tyr1095Cys), with no mutation identified in other ADPLD genes. (H) ADPLD-PRKCSH MRI Figure 1. These eight kidney and liver images illustrate the different genic and allelic forms of a 49-year-old man with predominant PLD of ADPKD and ADPLD, and the most frequent differential diagnosis. (A) ADPKD-PKD1T:MRI (HtTLV=7271 ml/min; liver resection was per- of a 45-year-old male patient with a truncating PKD1 mutation (c.4880_4883delATGT; formed after this MRI) and mild PKD (eight 2 p.Tyr1627fs), who has an eGFRCKDEPI=15.1 ml/min per 1.73 m and HtTKV=3853 ml/m. cysts in the left kidney). A right nephrectomy (B) ADPKD-PKD1NT: MRI of a 55-year-old woman with a PKD1 nontruncating mutation was performed at 42 years (atrophic cystic (c.2180T.C, p.Leu727Pro) with well preserved kidney function (eGFR=63.4 ml/min per kidney with suspected malignancy). The 1.73 m2) and HtTKV=439 ml/m. Significant PLD is present. (C) ADPKD-PKD2:MRIofa PRKCSH (c.1386T.G, p.Tyr462*) mutation 53-year-old man, with a PKD2 mutation (c.1057G.A, p.Glu353Lys), who has well pre- was identified. MRI, magnetic resonance served kidney function (eGFR=68.6 ml/min per 1.73 m2) and HtTKV=1245 ml/m. Note imaging; CT, computed tomography.

16 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 13–23, 2018 www.jasn.org BRIEF REVIEW details). Patients without a genetic diag- children diagnosed in utero or during ADPKD alone, often leading to renal insuf- nosis (untested or unresolved) would childhood at risk of early hypertension, ficiency in childhood.72–74 CGS individuals simply be termed ADPKD or ADPLD, urologic events, reduced eGFR, and with mosaicism can have milder, more typ- depending on the phenotype. This de- ESRD.4–6,63,64 We propose to use the ical ADPKD with TSC.74 scription of the disease phenotype and term ADPKDVEO when the diagnosis is etiology immediately provides renal made in utero or before 18 months, and prognostic information (Table 1). ADPKDEO when the diagnosis is made DIFFERENTIAL DIAGNOSIS FROM For most ADPKD and ADPLD genes before 15 years, in both cases excluding OTHER INHERITED RENAL CYSTIC there is no evidence of an allelic influence asymptomatic individuals diagnosed by DISEASES on the phenotype in the present small systematic familial screening or inciden- populations. However, there is strong ev- tally (see Table 3 for proposed diagnosis A number of other diseases can appear idence of allelic effects in ADPKD-PKD1. criteria). similar to ADPKD or ADPLD, although Although older data on relatively small In a proportion of these cases a specific are usually differentiated on clinical populations suggested a role for PKD1 cause of biallelic disease has been demon- grounds. Autosomal recessive polycystic mutation position influencing renal dis- strated; for instance, coinheritance of the kidney disease (ARPKD), associated with ease severity,59 more recent data from familial PKD1 mutation in trans with a biallelic PKHD1 mutations, although larger studies have convincingly shown second ULP PKD1 allele (Tables 1 and typically an infantile disease can manifest that mutation type is the key factor.3,14,55 4).4,41,43–45,48 Monoallelic ULP patients later in life with an ADPKD-like renal The Genkyst study demonstrated that are unlikely to develop renal insufficiency phenotype, but congenital hepatic fibrosis patients with PKD1 mutations predicted butmaydevelopmentasmallnumber rather than PLD usually differentiates the to truncate the protein experienced of cysts in adulthood (Figure 1D). The two.75 Monoallelic mutations to PKHD1 ESRD .12 years earlier than patients best characterized such allele is PKD1: have been described to cause increased with nontruncating mutations (see Table p.Arg3277Cys (Table 4).4,41,42,45,54 The kidney echogenicity and/or multiple small 1 footnote for definitions and Table 2 for combination of two ULP PKD1 alleles liver cysts (mimicking ADPLD) in approxi- 3 20,76 details). Because mutation type pro- can also result in ADPKDVEO with an ap- mately15%ofcarriers. However, with a vides potential prognostic information, parent negative family history (cysts carrier rate of approximately 1 in 70 it seems we propose to include this grouping in undetected in the monoallelic parents— that other genetic/environmental factors the nosology: ADPKD-PKD1T and often with lower resolution U/S analysis), must be necessary to reveal the monoallelic ADPKD-PKD1NT (Figure1,AandB,Table or adult onset ADPKD (Tables 1 and cystic phenotype. The association of PKD 1). The importance of mutation type was 4).41,42,45 This mechanism can involve with hyperinsulinic hypoglycemia was re- confirmed in a Canadian cohort, where PKD2; described as homozygosity of a cently described in 11 pedigrees and linked ADPKD-PKD1T patients had larger htTKV, PKD2 hypomorphic allele arising through to biallelic mutations (including a specific and in the HALT PKD clinical trial, where uniparental disomy.65 Inference from promoter mutation) of PMM2,encoding this group had a lower eGFR.14,55 The rea- mouse studies, and lack of described hu- the N-linked glycosylation , son for this phenotypic effect is that some man patients, indicates that biallelism of phosphomannomutase 2, again linking ADPKD-PKD1NT mutations have residual fully inactivating PKD1 or PKD2 mutations glycosylation defects and PKD.77 functional PC1.54,60,61 However, in ADPKD is not compatible with life,66,67 showing ADTKD because of MUC1 or UMOD genic or allelic information less clearly de- that these ULP alleles have residual func- mutations can result in the development fine the development of severe PLD, leading tion and indicating that a dosage/threshold of small renal cysts late in the disease, but to ADPKD-PKD1NT,ADPKD-PKD2,and mechanism best explains ADPKD.24,54,68,69 the lack of renal enlargement, and the ADPKD-GANAB patients with mild renal Rarely, digenic disease, involving PKD1 parallel decline of kidney size and kidney disease and severe PLD, where modifying ef- and PKD2, has been described, resulting in function with advancing disease, usually fects beyond the disease-causing gene have a more severe disease than for either variant differentiate them from ADPKD.78 significant influence (Figure 1, B and G).8 monoallelically, but not VEO.61,70,71 Path- ADTKD-HNF1B is associated with a ogenic alleles in other cystogenes may cause highly heterogeneous phenotypic spec- VEO PKD in combination with a PKD1 or trum, including maturity onset diabetes VERY EARLY ONSET (VEO) ADPKD PKD2 mutation, such as digenic disease of the young, a personal or familial history involving a PKD1 and HNF1B allele,43 em- of urogenital malformations, early onset When screening children at risk for phasizing the importance of comprehen- gout, and/or the presence of elevated liver ADPKD, renal cysts are detected in a ma- sive analysis of not only PKD1 and PKD2 or hypomagnesaemia, but dom- jority of affected individuals, even in early in these cases. Occasionally, a contiguous inant HNF1B mutations can sometimes childhood, but they do not necessarily gene syndrome (CGS) due to deletion of phenocopy ADPKD (Figure 1F).58,79 implicate a more severe prognosis.62 Con- PKD1 and the tuberous sclerosis complex Mutations to SEC61A1 have recently versely, early diagnosis can be secondary (TSC) gene TSC2 is associated with a more been identified in two families with to early symptoms, with “symptomatic” severe renal phenotype than TSC or ADTKD; glomerular cysts on renal

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Approximately7%ofADPKDand Table 3. Suggested diagnosis criteria for VEO and early onset ADPKD 50% of ADPLD pedigrees remain genet- Diagnostic Criteria ically unresolved.3,9,14,20,55 Variants to ADPKDVEO the existing genes, including missense In utero variants not considered pathogenic, Oligohydramnios deep intronic changes affecting splicing, . Hyperechoic enlarged kidneys (kidney length 2 SD) or mutations in the promoter regions, Between birth and 18 mo of age could explain some of these cases. Mo- Enlarged palpable kidneys saic, de novo mutations (mutation in the Plus at least one of the following criteria BP.95th percentile (or being under antihypertensive therapy) early embryo and so not present in all GFRa,90 ml/min cells) are sometimes associated with a Persistent and overt proteinuriab milder phenotype, and are often missed

ADPKDEO by conventional techniques due to their – Between 18 mo of age and 15 yr, at least one of the following criteria reduced dosage in leukocyte DNA.73,88 90 Enlarged palpable kidneys The recent identification of new ADPLD BP.95th percentile (or being under antihypertensive therapy) and ADPKD genes suggests that other a GFR ,90 ml/min genes encoding proteins involved in mat- b Persistent and overt proteinuria uration and trafficking of PC1 are strong a 102 Calculated using the Bedside Schwartz Equation (2009). candidates.15,20 bUrine excretion .4mg/m2 per hour or spot proteinuria .0.5 g/g of creatinine, confirmed on at least two samples. biopsy and multiple bilateral renal cysts disease.3,14,21,36,59,85 Severe PLD associated ESTIMATING THE PREVALENCE without renal enlargement were present in with PKD1, PKD2, PRKCSH,andSEC63 OF ADPKD AND ADPLD some family members.80 HANAC due to mutation is predominantly a female disease, COL4A1 mutations can also result in renal where growth moderates after menopause, Prevalence estimates can have important cysts, although the additional features, such suggesting a strong hormonal influence on implications for drug development, with as hematuria, muscles cramps or elevated the phenotype.8,9 It is unclear if there is a orphan diseases defined by a prevalence creatinine phosphokinase, tortuosity of the similar female bias associated with severe of ,1 per 2000.91 Older population– retinal artery, and brain small-vessel disease, PLD and the rarer ADPLD genes. based studies have estimated a lifetime usually allow for a differential diagnosis.81 The ADPKD-PKD1NT population risk of ADPKD at 1 per 1000, or even Syndromic forms of PKD can sometimes encompasses a large spectrum, from higher if autopsies—that likely included prove challenging as a differential diagnosis fully inactivating mutations (similar to patients with few kidney and liver cysts from ADPKD. Oro-facial-digital syndrome ADPKD-PKD1T) to ULP alleles associ- and excellent renal prognoses plus type 1 is a rare X-linked dominant disor- ated with mild PKD (Figure 1D).86 The other phenocopying disorders—are der with male prenatal lethality, where the Canadian cohort suggested that PKD1 taken into consideration.92,93 More re- monoallelic female renal presentation can patients with inframe indels had renal cent population-based minimum point be indistinguishable from ADPKD, although severity intermediate between missense prevalence estimates of 2.9 and 3.3 per extrarenal manifestations should orient the and PKD1T.55 In HALT PKD, ADPKD- 10,000, reflecting individuals with clini- diagnosis.82,83 TSC because of mutation to PKD1NT patients were further classified cally significant disease, fall below the TSC1 or TSC2 (without the CGS) is pheno- into strongly or weakly predicted muta- orphan threshold.94–96 ADPKD-PKD2 typically heterogeneous, with the develop- tion strength groups (MSG2 or MSG3, re- genetic prevalence in European individ- ment of benign tumors in many organs, but spectively) using an in silico algorithm. uals from the ExAC database was calcu- can occasionally present with kidney cysts MSG3, but not MSG2 patients, had signif- lated at 1.64 per 10,000, suggesting a with only discreet dermatologic features.84 icantly higher eGFR and lower HtTKV higher prevalence of the total ADPKD In each of these cases, genetic analysis of a than ADPKD-PKD1T.14 However, no au- population.97 ADPLD prevalence, esti- panel of PKD genes can better reveal the full tomated schema to assign MSG scores to mated in a single study at 1 per 158,000, etiology and aid diagnostics. PKD1NT variants is yet available and so at is likely underestimated, because many this stage we have not included these affected individuals probably remain groups into the classification. However, asymptomatic and undiagnosed.98 Con- OTHER INFLUENCES ON as mutation screening becomes more ducting a combined analysis of clinical PHENOTYPE, AND GENETICALLY widespread, variants are better collated, records, imaging, and genetic data in a UNRESOLVED CASES in silico tools are improved, and in vitro geographically circumscribed area assays of PKD1 variants are developed, would be invaluable to refine prevalence Accumulating data in ADPKD indicates better classification of PKD1NT variants estimates for the total population and that males tend to have more severe renal should be possible.14,56,87 genic/allelic groups.

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Table 4. Ultra low penetrant (ULP) alleles of PKD1 and PKD2 involved in biallelic ADPKD ULP Allelea Other Mutant Allele Phenotype Description, Age at Phenotype Ref. PKD1 c.9829C.T (p.Arg3277Cys) None Pedigree M34–6 relatives, 0–7 kidney cysts, 41 28–79 yrb PKD1 c.9829C.T (p.Arg3277Cys) Pedigree M34- ESRD in two siblings, 41 62 and 75 yr Pedigree PK10362- ESRD 76 yr 36 Pedigree PK11509- ESRD 48 yr 36 PKD1 ex1–5del EHK, 22 pw (TOP) 4 PKD1 c.6472C.T (p.Gln2158*) EHK (.10 SD), at birth; HTN, 5 m; 41 eGFR=56, 17 yr PKD1 c.6658C.T (p.Arg2220Trp)c Two siblings EHK, RD; HTN 0 m, 42 eGFR=70 or 65 at 1 or 8 yr PKD1 c.7483T.C (p.Cys2495Arg) EHK, 17 pw, birth MEK, SC 2.1, 45 4d PKD1 c.9563A.G (p.Asn3188Ser)c PKD1 c.9563A.G (p.Asn3188Ser) Father, BCK, Sibling 1, EHK, 22 pw, 41 eGFR 67, 15.5 yr Sibling 2, BCK 9 yr, eGFR 86, 15 yr PKD1 c.5848G.A (p.Val1950Met)c PKD1 c.8362_8363ins34 (p.Ser2788fs) EHK, OH; double nephrectomy, RD, 44 neonatal demise PKD1 c.[3133C.G;4709C.T] PKD1 c.[3133C.G;4709C.T] Sibling 1- EHK, ESRD 8.5 yr 42 (p.[Val1045Met;Thr1570Met]) (p.[Val1045Met;Thr1570Met]) Sibling 2- EHK, 18 pw (TOP) None Grandfather: Few renal cysts at age? PKD1 c.5305C . T (p.His1769Tyr) PKD1 c.6727C . T (p.Gln2243*) Sibling 1- MEK, ESRD 29 yr 103 Sibling 2- MEK, eGFR 91, 25 yr None Father: 7 small renal cysts, 58 yr PKD1 c.6763C.T (p.Arg2255Cys) PKD1 c.8259C.G (p.Tyr2753*) EK, CRI, age? 43 None Sibling 1- SIE, age?; Sibling 2- SIE, few cysts, age? PKD1 c.12413G.A (p.Arg4138His)c PKD1 c.4199del (p.Leu1400fs) two siblings, MEK at birth, RD, HTN 43 PKD1 c.3828G.A (p.Val1274Met)c PKD1 c.3828G.A (p.Val1274Met) Sibling 1- EHK, neonatal, cyst, 8 yr, HTN, 43 Sibling 2- EHK, multiple cysts, 7 yr, Sibling 3- EHK, multiple cysts, 17 m PKD1 c.9884A.G (p.Asn3295Ser) PKD1 c.10232G.A (p.Trp3411*) EHK, 22 pw 4 PKD1 c.9548G.A (p.Arg3183Gln) PKD1 c.11614G.T (p.Glu3872*) EHK (6 SD), 22 pw 4 PKD1 c.12161C.T (p.Ser4054Phe) PKD1 c.7978G.T (p.Asp2660Tyr) EHK (4 SD), 26 pw 4 PKD1 c.11834C.T (p.Thr3945Met)c PKD1 c.2180T.C (p.Leu727Pro) EHK (14 SD), 15 pw (TOP) 4 PKD1 c.8129C.A (p.Thr2710Asn) PKD1c.1010_1013dup (p.Leu339Glyfs*33) EHK (3 SD), 17 pw 4 PKD1 c.5830G.A p.Gly1944Arg)c PKD1c.5517G.T (p.Trp1839Cys) EHK (2 SD), 25 pw 4 PKD1 c.6173G.A (p.Gln2058Arg)c PKD1 c.9562A.G (p.Asn3188Asp) EHK (14 SD), at birth; eGFR=56, 20 yr 4 PKD1 c.12074A.G (p.Glu4025Gly) PKD1 c.2582G.A (p.Trp861*) EHK (10 SD), 22 pw; CKD3a, 4 yr 4 PKD1 c.4831G.A (p.Val1611Ile) PKD1 c.12503dup (p.Ser4169Leufs*41) EHK (3 SD), 22 pw 4 PKD2 c.1967T.G (p.Leu656Trp)c,d,e PKD2 c.1967T.G (p.Leu656Trp) EHK (approximately 18 SD), at birth, 65 HTN, 2m; eGFR=52, 18 yr EHK, enlarged hyperechoic kidneys; pw, pregnancy weeks; TOP, termination of pregnancy; HTN, hypertension; RD, respiratory distress; MEK, massively enlarged kidneys; BCK, bilateral cystic kidneys; OH, oligohydramnios; SIE, slight increased echogenicity. aOther described examples where the high frequency of the ULP allele in normal individuals or in silico analysis makes the ULP allele an unlikely cause of the VEO PKD are not listed. bDetected by computed tomography or magnetic resonance imaging. cIdentified alone in one parent, no cysts detected on ultrasound. dHomozygosity due to maternal isodisomy. e Likely ADPKDVEO but no details about presence or not of oligohydramnios and evolution after diagnosis (hypertension/kidney function/overt proteinuria).

CLINICAL IMPLICATIONS information with the sex and clinical infor- marker.33 Multidisciplinary approaches mation(earlyhypertensionandurinary tract involving clinical, imaging, and genetic Stratifying the ADPKD population is a infections), the PROPKD score, has shown data should now be favored as they help prerequisite to the personalization of pa- strong renal prognostic value.36,99 Age- diagnostics, including the characteriza- tient care. Combining genic and allelic adjusted TKV is also a valuable prognostic tion of atypic clinical presentations,

J Am Soc Nephrol 29: 13–23, 2018 Genetics of ADPKD and ADPLD 19 BRIEF REVIEW www.jasn.org while predicting the evolution of patients 6. Zerres K, Rudnik-Schöneborn S, Deget F: Kidney Disease Group; Consortium for Ra- with ADPKD, which is key to targeting German working group on paediatric ne- diologic Imaging Studies of Polycystic Kidney phrology: Childhood onset autosomal domi- Disease; Harris PC: Mutations in GANAB, therapies. Genic and allele information nant polycystic kidney disease in sibs: Clinical encoding the glucosidase IIalpha subunit, may also be important in the future as picture and recurrence risk. J Med Genet 30: cause autosomal-dominant polycystic kidney specific treatments proximal to the basic 583–588, 1993 and liver disease. Am J Hum Genet 98: 1193– defect are developed, as is occurring in 7. Hogan MC, Abebe K, Torres VE, Chapman 1207, 2016 other common genetic diseases.100 AB, Bae KT, Tao C, Sun H, Perrone RD, 16. 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