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Received: 21.2.2019; Editorial decision: 19.7.2019

Nephrol Dial Transplant (2021) 36: 305–329doi: 10.1093/ndt/gfz173Advance Access publication 18 November 2019

Targeted broad-based genetic testing by next-generationsequencing informs diagnosis and facilitates managementin patients with kidney diseases

M. Adela Mansilla1, Ramakrishna R. Sompallae1, Carla J. Nishimura1, Anne E. Kwitek2, Mycah J. Kimble1,Margaret E. Freese3, Colleen A. Campbell1, Richard J. Smith1,3,4 and Christie P. Thomas3,4,5

1Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA, USA, 2Physiology, Medical College of Wisconsin, Iowa City, IA, USA,3Internal Medicine, University of Iowa, Iowa City, IA, USA, 4Pediatrics, University of Iowa, Iowa City, IA, USA and 5Veterans Affairs MedicalCenter, Iowa City, IA, USA

Correspondence and offprint requests to: Richard J. Smith; E-mail: [email protected], Christie P. Thomas;E-mail: [email protected]

A B S T R A C T

Background. The clinical diagnosis of genetic renal diseasesmay be limited by the overlapping spectrum of manifestationsbetween diseases or by the advancement of disease where cluesto the original process are absent. The objective of this studywas to determine whether genetic testing informs diagnosis andfacilitates management of kidney disease patients.Methods. We developed a comprehensive genetic testing panel(KidneySeq) to evaluate patients with various phenotypes in-cluding cystic diseases, congenital anomalies of the kidney andurinary tract (CAKUT), tubulointerstitial diseases, transportdisorders and glomerular diseases. We evaluated this panel in127 consecutive patients ranging in age from newborns to81 years who had samples sent in for genetic testing.Results. The performance of the sequencing pipeline forsingle-nucleotide variants was validated using CEPH (Centre

de’Etude du Polymorphism) controls and for indels usingGenome-in-a-Bottle. To test the reliability of the copy num-ber variant (CNV) analysis, positive samples were re-sequenced and analyzed. For patient samples, a multidiscipli-nary review board interpreted genetic results in the contextof clinical data. A genetic diagnosis was made in 54 (43%)patients and ranged from 54% for CAKUT, 53% for ciliopa-thies/tubulointerstitial diseases, 45% for transport disordersto 33% for glomerulopathies. Pathogenic and likely patho-genic variants included 46% missense, 11% nonsense, 6%splice site variants, 23% insertion–deletions and 14% CNVs.In 13 cases, the genetic result changed the clinical diagnosis.Conclusion. Broad genetic testing should be considered in theevaluation of renal patients as it complements other tests andprovides insight into the underlying disease and its management.

VC The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercialre-use, please contact [email protected] 305

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Keywords: copy number variants, genetic kidney disease, mas-sively parallel sequencing, targeted gene panel

A D D I T I O N A L C O N T E N T

An author video to accompany this article is available at:https://academic.oup.com/ndt/pages/author_videos.

I N T R O D U C T I O N

The kidney is a complex organ that maintains physiological ho-meostasis through a myriad of complex processes that includethe excretion of excess water, ingested drugs, toxins and meta-bolic waste products, the regulation of acid–base balance, thereclamation or elimination of various salts, and the synthesis ofa variety of endocrine hormones to control blood pressure,erythropoiesis and bone mineralization. Disrupting this func-tion leads to a broad spectrum of disease phenotypes. At one ex-treme are diseases that manifest as well-recognized Mendeliandisorders such as Liddle syndrome, which is characterized byhypertension with hypokalemia from unregulated hyperactivityof the epithelial sodium channel in the connecting tubule andcollecting duct [1]. At the other extreme are diseases in which amore global decline in renal function leads to chronic kidneydisease (CKD) with a reduction in glomerular filtration rate, re-tention of urea, phosphorus and potassium, and the developmentof anemia and bone disease. The development of CKD may blurclues to the inciting insult even with extensive laboratory testing,renal imaging and renal histological examination [2].

Over the past decade, a number of discoveries relevant to re-nal diseases have improved our understanding of the ciliopa-thies [3], focal segmental glomerulosclerosis (FSGS) [4],steroid-resistant nephrotic syndrome [5, 6] and congenitalanomalies of the kidney and urinary tract (CAKUT) [7, 8]. Inrecent years, the advancement of next-generation sequencinghas facilitated the simultaneous interrogation of multiple genesfor molecular diagnosis within many disease categories includ-ing those that cause a variety of renal diseases [9, 10]. In addi-tion, exome sequencing (ES) has been used to diagnosemonogenic renal diseases [11, 12]. The diagnostic success ofdisease-focused panels may be limited by difficulty in pheno-typing renal diseases into specific categories. Similarly, ES maynot be sensitive enough to detect variants in duplicated regions,such as the proximal portion of PKD1. We sought to test theclinical relevance of broad-based genetic testing that targetsgenes across a wide variety of renal disease phenotypes to in-form diagnosis and facilitate management of the renal patient.Using a panel of 177 genes, we tested 127 consecutive renalpatients whose samples we received and in this diverse cohortmade a genetic diagnosis in 54 patients. Remarkably, in 13patients, the genetic findings changed the clinical diagnosis.

M A T E R I A L S A N D M E T H O D S

Study design

This was a retrospective study of the diagnostic accuracy ofcomprehensive genetic testing panel used a cohort of 127

consecutive patients where samples were sent to the Universityof Iowa Institute of Human Genetics for gene screening. Therewere no exclusion criteria. Patients were classified, based onclinical history provided, into the following broad disease sub-types: ciliopathies/tubulointerstitial diseases, CAKUT, tubulartransport disorders and glomerulopathies. American College ofMedical Genetics (ACMG) criteria were used to classify geneticvariants as pathogenic, likely pathogenic, variant of unknownsignificance (VUS), likely benign and benign [13].

Gene selection, platform design and validation, andpatient recruitment

Genes implicated in a large number of renal diseases were se-lected for inclusion in the kidney disease panel (KidneySeq v1)and grouped by renal phenotype (e.g. ciliopathy, glomerulardiseases and CAKUT). Targeted capture of coding exons andsplice sites was optimized using RNA baits selected withAgilent’s SureDesign online software, incorporating 4-foldprobe density and 25-base pairs of flanking intronic sequence.Performance metrics were assessed by studying 31 genomicDNA samples from the CEPH consortium (Centre de’Etude duPolymorphism) using results to improve depth-of-coverage(Supplementary data, Table S1). Additional genes were alsoadded to increase the genetically relevant search space. Theupdated panel (KidneySeq v2) was used in the diagnostic evalu-ation of sequentially accrued samples from patients with renaldisease (Table 1 and Supplementary data, Table S2). There wereno exclusionary criteria.

Library preparation, targeted genomic enrichment andmassively parallel sequencing

After preparing libraries from patient-derived gDNA, librarypreparation, targeted genomic enrichment and massively paral-lel sequencing (MPS) were completed as we have described[14]. In brief, libraries were prepared using a modification ofthe solution-based Agilent SureSelect target enrichment system(Agilent Technologies, Santa Clara, CA, USA) with liquid-handling automation. Hybridization and capture with RNAbaits were followed by a second amplification. Before poolingfor sequencing, all samples were bar coded and multiplexed.Sequencing was done using Illumina HiSeq (pool of 48 sam-ples) or MiSeq (pools of five samples) instrumentation(Illumina Inc., San Diego, CA, USA). Sanger sequencing wasused to amplify and resolve exons 1–34 of PKD1 [15, 16].

Bioinformatics analysis

Data analysis was performed on dedicated computingresources maintained by the Iowa Institute of Human Geneticsusing a standardized workflow for sequence analysis and vari-ant calling [14]. The freebayes variant caller was used to identifyvariants in PKD1. Variant annotation was performed with acustom-built reporting tool.

Variant filtering

Library quality was based on the total number of reads persample and coverage at 30� or greater, excluding low-qualityvariants [depth<10 or quality by depth (QD) <5] and

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Table 1. KidneySeq v2 gene list by disease category

Ciliopathies/tubulointerstitial diseasesAlagille syndrome NOTCH2Autosomal recessive polycystic kidney disease PKHD1Autosomal dominant polycystic kidney disease PKD1, PKD2Autosomal dominant tubulointerstitial kidney disease HNF1B, REN, UMODBardet–Biedl syndrome (BBS) ARL6, BBS1, BBS2, BBS4, BBS5, BBS7, BBS10, BBS12, CEP290,

MKKS, PTHB1, TRIM32, TTC8COACH syndrome CC2D2A, RPGRIP1L, TMEM67HANAC syndrome COL4A1Jeune syndrome IFT80, IFT140, DYNC2H1, NEK1, TTC21BJoubert syndrome AHI1, ARL13B, ATXN10, CC2D2A, CEP290, CEP41, CSPP1,

INPP5E, KIF7, NPHP1, OFD1, RPGRIP1L, TMEM216, TCTN1,TMEM138, TMEM237, TMEM67, TTC21B

Juvenile nephronophthisis (JN) AHI1, ATXN10, IQCB1, CEP290, GLIS2, INVS, NEK8, NPHP1,NPHP3, NPHP4, RPGRIP1L, TMEM67, TTC21B, WDR19,XPNPEP3

Meckel syndrome (MKS)/Meckel–Gruber syndrome B9D1, B9D2, CC2DA, CEP290, MKS1, NPHP3, RPGRIP1L,TCTN2, TMEM216, TMEM67

Medullary cystic kidney disease 2 UMODOro-facial-digital syndrome 1 OFD1Renal cysts and diabetes syndrome HNF1BSerpentine fibula with polycystic kidney disease (SFPKS)/Hajdu–Cheney

syndrome (HJCYS)NOTCH2

Sensenbrenner syndrome/(CED) IFT122, IFT43, WDR19, WDR35Senior–Loken syndrome (JN with retinitis pigmentosa) CEP290, IQCB1, NPHP1, NPHP3, NPHP4, WDR19

Disorders of tubular ion transportApparent mineralocorticoid excess, syndrome of HSD11B2

APRT deficiency APRTAutosomal dominant hypocalcemia, 6 Bartter syndrome CASRBartter syndrome BSND, CLCNKA, CLCNKB, KCNJ1, SLC12A1Cystinosis CTNSCystinuria SLC3A1, SLC7A9Dent disease CLCN5, OCRLDistal renal tubular acidosis ATP6V0A4, ATP6V1B1, SLC4A1Familial hypertension with hyperkalemia (Gordon syndrome),

Pseudohypoaldosteronism IICUL3, KLHL3, WNK1, WNK4

Gitelman syndrome CLCNKB, SLC12A3Hypophosphatemic rickets DMP1, CLCN5, ENPP1, FGF23, PHEX, SLC34A3Isolated proximal renal tubular acidosis—generalized proximal defect

(Fanconi syndrome)ATP7B, CLCN5, CTNS, EHHADH, FAH, HNF4A, SLC34A1

Liddle syndrome (pseudo hyperaldosteronism) SCNN1B, SCNN1GNephrogenic diabetes insipidus (NDI) AQP2, AVPR2Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) AVPR2Primary hyperoxaluria AGXT, GRHPR, HOGA1Pseudohypoaldosteronism I (PHA I) NR3C2, SCNN1A, SCNN1B, SCNN1GRenal glucosuria SLC5A2Renal hypomagnesemia CLDN16, CLDN19, CNNM2, EGF, HNF1B, TRPM6Renal tubular acidosis, proximal, with ocular abnormalities SLC4A4

Glomerular diseasesAlport syndrome COL4A3, COL4A4, COL4A5Alstrom syndrome ALMS1Congenital nephrotic syndrome (Finnish type) NPHS1DDS; Frasier syndrome WT1Diffuse mesangial sclerosis ARHGDIA, PLCE1, WT1Epstein–Fechtner syndrome (renal disease with macrothrombocytopenia) MYH9Fabry disease GLAFSGS–AD/XL ACTN4, ANLN, ARHGAP24, CD2AP, COL4A3, COL4A4,

COL4A5, INF2, LMX1B, PAX2, TRPC6, WT1FSGS–AR APOL1, CRB2, MYO1E, NPHP4, TTC21BFSGS/steroid-resistant nephrotic syndrome (SRNS)–AR ADCK4, ALG1, ARHGDIA, CUBN, LAMB2, NPHS1, NPHS2,

PLCE1, PDSS2, PMM2, PTPRO, SCARB2, ZMPSTE24Galloway–Mowat syndrome WDR73Glomerulopathy with fibronectin deposits FN1Hereditary systemic or renal amyloidosis APOA1, B2M, FGA, LYZ, NLRP3

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Unbiased testing advances the diagnosis of renal diseases 307

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common variants with a minor allele frequency (MAF) >1% inany population (except for known risk alleles).Nonsynonymous single-nucleotide variants (SNVs), canonicalsplicing changes and insertion–deletions (indels) were retained.Reference databases routinely queried included the HumanGene Mutation Database, ClinVar, the autosomal dominantpolycystic kidney disease (ADPKD) mutation database, theARUP (COL4A5) database and our in-house Renal VariantDatabase (RVD). GERPþþ, PhyloP, MutationTaster,PolyPhen2, SIFT and LRT were used to calculate variant-specific pathogenicity scores as described [14].

Copy number variant analysis

Copy number variant (CNV) analysis was performed usingExomeCopy and ExomeDepth [17]. CNV calls from both

programs were manually curated and validated if breakpointswere identified.

Sanger sequencing

Sanger sequencing was performed for platform validation,for PKD1 testing and to confirm pathogenic variants, designingprimers using Primer 3 (http://bioinfo.ut.ee/primer3-0.4.0/primer3/) [14].

Variant interpretation

A multidisciplinary board was held semimonthly to discussall genetic results on a patient-by-patient basis in the context ofthe available clinical data. Variants were classified followingACMG guidelines. Variants with a MAF>1% were classified as‘benign’ with a few notable exceptions (APOL1 G1 and G2alleles). Variants reported as ‘pathogenic’ in the literature with

Table 1. Continued

Muckle–Wells syndrome NLRP3Nail patella syndrome LMX1BNephrotic syndrome, steroid sensitive PLCG2Pierson syndrome (nephrotic syndrome with microcoria) LAMB2Thin basement membrane disease (benign familial hematuria) COL4A3, COL4A4

CAKUTBranchio-oto-renal syndrome EYA1, SIX1, SIX5CAKUT with VACTERL TRAP1Cogan oculomotor apraxia NPHP1Common CAKUT AGTR1, AGTR2, CHD1L, DSTYK, EYA1, GATA3, HNF1B,

PAX2, RET, ROBO2, SALL1, SIX2, SIX5, TRAP1Fraser syndrome FRAS1, FREM2, GRIP1Hypoparathyroidism, sensorineural deafness and renal dysplasia GATA3Isolated renal hypo-dysplasia BMP4, DSTYK, FGF20, HNF1B, PAX2, RET, SALL1, SIX2Isolated renal hypoplasia and renal-coloboma syndrome (papillorenal

syndrome)PAX2

Isolated renal hypoplasia RET, UPK3Kallmann syndrome ANOS1Mayer–Rokitansky–Kuster–Hauser syndrome WNT4Multicystic dysplastic kidney CHD1L, HNF1B, ROBO2, SALL1Posterior urethral valves CHD1L, HNF1B, ROBO2, SALL1, SIX2Renal cysts and diabetes syndrome HNF1BRenal tubular dysgenesis ACE, AGT, AGTR1, RENTownes–Brocks syndrome SALL1Unilateral renal agenesis DSTYK, HNF1B, RET, SALL1UPJ obstruction DSTYK, EYA1, HNF1B, RET, ROBO2, SALL1UVJ obstruction CHD1L, PAX2, SIX5Vesicoureteral reflux DSTYK, EYA1, GATA3, HNF1B, RET, ROBO2, SALL1, SOX17,

TNXB, UPK3AOther

Acrorenoocular syndrome (Okihiro syndrome) SALL4Mitochondrial cytopathy COQ2Pallister–Hall syndrome GLI3Rubinstein–Taybi syndrome CREBBPSchimke immuno-osseous dysplasia SMARCAL1SERKAL syndrome (46XX sex reversal with dysgenesis of kidneys, adrenaland lungs)

WNT4

Simpson–Golabi–Behmel syndrome GPC3Smith–Lemli–Opitz syndrome DHCR7Tuberous sclerosis TSC2Williams syndrome 7q 11.23


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http://bioinfo.ut.ee/primer3-0.4.0/primer3/

supporting functional evidence were classified as ‘pathogenic’.The ‘likely pathogenic’ classification was assigned to missensevariants with pathogenicity scores �4 (based on GERPþþ,PhyloP, MutationTaster, PolyPhen2, SIFT and LRT) if theywere also ultra-rare and in a disease-related functional domain.Novel or rare variants that changed protein sequence but hadan unknown impact on protein function were classified asVUSs. Based on the clinical phenotype and the genotypic find-ings, clinical correlation and segregation analysis wererecommended.

Institutional Review Board

The study was approved by the Institutional Review Board(IRB No. 201805825) for human subject research and informedconsent was waived. The study adheres to the Principles ofMedical Research as stated in the Declaration of Helsinki.

R E S U L T S

Performance metrics

Performance and validation of KidneySeq v1 using 31CEPH samples showed that >70% of sequence reads over-lapped target regions with a mean coverage of�400�;>99% ofbases were covered by at least 30 reads (30�). This thresholdwas achievable with at least 5 million reads per sample(Supplementary data, Figure S1). Targeted regions covered at lessthan 30� were Sanger sequenced; no additional variants wereidentified (Supplementary data, Table S3). These performancemetrics were used to refine the panel by changing probe density.

Variant analysis

Call accuracy in the 31 CEPH controls was determined bySanger sequencing 29 variants with MAF>1% and 32 variantswith QD<10 in all samples (Supplementary data, Table S4);256 variants that were either heterozygous or homozygous al-ternate were identified (Supplementary data, Figure S2). All val-idated variants with a QD<5 were false positives. BetweenQD>5 and QD<10, there were false-positive calls for bothSNVs and indels. Of the 1643 sites, there were 252 true posi-tives, 4 false positives, 1387 true negatives and no false nega-tives. Specificity (99.71), sensitivity (100), and positive (98.44)and negative (100) predicted values were very high(Supplementary data, Tables S4 and S5).

Validation of sequencing and analysis pipeline

A high-density SNP array was used to interrogate the CEPHsample, NA12287 (1421-14). A comparison of genotype callsfrom the SNP array and KidneySeq v1 identified only one dis-cordant variant from the 3008 identified (Supplementary data,Figure S3a). Through Sanger confirmation, we verified that theKidneySeq v1 variant call was correct and the SNP array was in-correct. To validate indels, we used Genome-in-a-Bottle(GIAB), which predicts 314 indels in the KidneySeq v1 targetedregions. All predicted indels were identified by KidneySeq v1 inaddition to two other indels at QD>5 not reported in the GIABreference sequence but confirmed by Sanger sequencing(Supplementary data, Figure S3b). To test the reliability and sen-sitivity of the CNV analysis workflow, positive samples were re-sequenced and re-analyzed. All known CNVs were detected suc-cessfully on the repeat samples (Supplementary data, Table S6).

PKD1 gene proximal region

The duplicated region of PKD1 (exons 1–34) was Sanger se-quenced to verify variant detection. The panel detected 36 var-iants in the homologous region of the PKD1 gene in sevenpatients selected for this validation. Overall, 94.4% (34 of 36) ofthese variants were verified by Sanger sequence. The variantdetected only by MPS (the same variant was detected in twopatients) was a false positive in exon 15. No false negatives weredetected by Sanger sequencing.

Patients

Genetic testing was completed on 127 patients (77 males).The most common indication was FSGS (17 patients), followedby medullary cystic kidney disease/nephronophthisis (14

Table 2. Indications for testing

CAKUTBranchio-oto-renal syndrome 2HNF1-b 1Multicystic dysplastic kidney 3Papillorenal syndrome 1Renal hypo/dysplasia 6Unspecified 5Total 18

Ciliopathy/tubulointerstitialADPKD 7ARPKD 3Medullary cystic kidney disease/nephronophthisis 14Orofacial digital syndrome 1Renal cysts 5Total 32

Tubular ion transportApparent mineralocorticoid excess 1Bartter/Gitelman 9Cystinuria 1Dent 5Fanconi 2Hypercalcemia 3Hypokalemia 2Hypomagnesemia 3Hypophosphatemia 3Kidney stones 2Liddle syndrome 2NDI 3Pseudohypoaldosteronism I 2Renal tubular acidosis 2Total 40

GlomerulopathyAlport/Alport like 10FSGS 17Nephrotic proteinuria/nephrotic syndrome 9Other glomerular 2Total 40

OtherNephrogenic rests 1Nonrenal 1No information 5Unclassified kidney disease 10Total 17

Some patients had multiple laboratory abnormalities or clinical diagnosis that is listed indi-vidually, resulting in larger totals. ARPKD, autosomal recessive polycystic kidney disease.


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Table 3. Clinical renal samples: all patients with indication for testing, family history, disease type and demographics; family history, when known, areshown as positive (Y) or negative (N)

Case Indication for testing Family history Disease categorya,b Sex Age (years) Ethnicity

1 Bilateral multicystic dysplastic kidneys Y 1 F 6 Hispanic2 Renal dysplasia Unknown 1 M 1 Caucasian, non-

Hispanic3 Stage 5 (CKD), hearing loss Unknown 4 M 37 Asian4 FSGS at age 40 years N 4 M 66 Caucasian, non-

Hispanic5 Proteinuria, FSGS Y 4 M 54 African/African-

American, non-Hispanic

6 Alport syndrome Y 4 M 34 White7 Dent disease (NDI, failure to thrive) Unknown 3 M 1 Caucasian, Hispanic or

Latino8 Nephronophthisis Y 2 F 10 African/African-

American9 FSGS Unknown 4 M 54 African/African-

American10 Nephrotic syndrome Unknown 4 M 3 Hispanic or Latino11 Medullary cystic kidney disease Unknown 2 M 27 Caucasian, non-

Hispanic12 Hypomagnesemia Unknown 3 F 11 Not provided13 FSGS Unknown 4 M 58 Caucasian, non-

Hispanic14 Medullary cystic kidney disease/

nephronophthisisUnknown 2 M 31 Caucasian

15 Hypercalcemia, hypocalciuria N 3 F 81 Caucasian16 Dilated cardiomyopathy and

hypomagnesemiaN 3 M 3 Caucasian

17 Fanconi syndrome, hypophosphatemicrickets

Unknown 3 M 2 Caucasian, aboriginal

18 ESRD, primary FSGS Unknown 4 M 55 Caucasian19 Severe CAKUT Unknown 1 M <1 Caucasian, Hispanic or

Latino20 Alport syndrome Unknown 4 M 5 Asian (India), non-

Hispanic21 Hypercalcemia, hypercalciuria, short

statureUnknown 3 M 2 Caucasian, non-

Hispanic22 Interstitial nephritis Unknown 2 F 10 Caucasian23 U/S prenatal echogenic kidneys, postna-

tal bilateral cysts, HNF1B diseaseUnknown 1 M <1 Caucasian, non-

Hispanic24 Bartter syndrome or other Unknown 3 M 1 Not provided25 ESRD, tubulointerstitial disease Y 2 M 51 African/African-

American26 Bilateral hypoplastic dysplastic kidneys Unknown 1 M <1 Caucasian, Hispanic or

Latino27 Microhematuria, Alport or TBM disease Unknown 4 M 2 Caucasian, Hispanic or

Latino28 FSGS or MCKD Y 2, 4 M 60 African/African-


29 Alport or TBM disease Unknown 4 M 18 Caucasian, non-Hispanic

30 FSGS, SRNS, hypoalbuminemia Unknown 4 M 17 Caucasian, non-Hispanic

31 FSGS or Dent disease. Nephroticrangeproteinuria, global glomerulosclerosis

Unknown 3, 4 M 18 African/African-American

32 ADTKD, tubular proteinuria, no signs ofFanconi

Y 2 M 18 Unknown

33 Alport syndrome. Hearing loss,microscopic hematuria, CKD

Unknown 4 M 12 Caucasian

34 Renal agenesis/hypoplasia ornephronophthisis

Y 1, 2 F 16 Hispanic or Latino

35 Gitelman/Bartter syndrome Unknown 3 F 17 Caucasian

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Table 3. Continued


36 Bilateral multicystic dysplastic kidneys,perinatal death

Unknown 1 M 0b Unknown

37 Bartter syndrome, NDI or Dent disease.Polyuria, polydipsia, hypercalciuria,medullary nephrocalcinosis

Unknown 3 M 16 Caucasian, non-Hispanic

38 Pseudohypoaldosteronism.Hyperkalemia, polyuria

Unknown 3 M 0b Hispanic or Latino

39 Multicystic bilateral kidneys Unknown 1 M 0b Caucasian, non-Hispanic

40 Apparent mineral corticoid excess Unknown 3 M 2 Not provided41 Bartter syndrome. Polyuria, metabolic

alkalosisUnknown 3 F 3 Caucasian, non-

Hispanic42 Liddle syndrome. Early onset

hypertension and hypokalemiaY 3 F 19 Caucasian, Hispanic or

Latino43 PKD (bilateral renal cysts and

hypertension)Unknown 2 M 15 Hispanic or Latino

44 NDI, medullary nephrocalcinosis,vesicoureteral reflux, hypophosphatemia

Unknown 3 F 3 Caucasian, non-Hispanic

45 Cystinuria Y 3 F 19 Caucasian46 FSGS or minimal change disease.

Persistent proteinuriaUnknown 4 M 5 Caucasian, non-

Hispanic47 Hypokalemia, hypomagnesemia, high

urinary Na and K, prior diagnosis of NDIUnknown 3 F 59 Caucasian, non-

Hispanic48 Hypotonia, dysmorphic features,

developmental delay, obesityUnknown 5 F 2 Caucasian, non-

Hispanic49 Horseshoe kidney asymptomatic;

daughter, son perinatal/fetal demisewith CAKUT

Y 1 F 33 Caucasian, NativeAmerican, non-Hispanic

50 Proximal tubulopathy or Dent orhypophosphatemic rickets,nephrocalcinosis, small stature

Unknown 3 F 13 Asian, non-Hispanic

51 FSGS, ESRD, post-kidney transplant Unknown 4 M 15 Hispanic or Latino52 PKD1, PKD2, HNF1B Unknown 2 M 6 Hispanic or Latino53 Renal cysts, family history of hereditary

nephritisN 2 F 49 Asian, non-Hispanic

54 Polycystic kidney disease, undescendedtestes, HTN

N 2 M <1 Caucasian, non-Hispanic

55 ESRD, FSGS Y 4 M 64 African/African-American

56 HTN, AKI, LVH, congenital nephroticsyndrome or ARPKD

Unknown 2, 4 F <1 Not provided

57 Moderate CKD Unknown 5 M 1 Not provided58 Not provided Unknown 5 F 16 Not provided59 Bartter/Gitelman syndrome,

hypokalemia, hypomagnesemia andmetabolic alkalosis

Unknown 3 M 12 Not provided

60 Nephronophthisis or MCKD Y 2 M 58 Caucasian, non-Hispanic

61 Polycystic kidney disease Unknown 2 F 51 African/African-American

62 FSGS or MCKD Y 2, 4 M 56 African/African-American

63 FSGS/multicystic dysplastic kidney Y 1, 4 M 15 Caucasian, non-Hispanic

64 Hyperplastic nephrogenic rests, featuresseen with underlying syndromes suchas Beckwith–Wiedemann

Unknown 5 F <1 Not provided

65 Hypophosphatemic rickets; distal renaltubular acidosis; isolated proximalrenal tubular acidosis, generalizedproximal defect

N 3 F 0b Hispanic or Latino

66 FSGS Unknown 4 F 10 African/African-American, non-Hispanic

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Table 3. Continued


67 Horseshoe kidney, dysmorphic features,VSD

Y 1 F <1 Egyptian

68 Kidney stones, paresthesias, hypercalciuria,hypoparathyroidism, ESRD

Y 3 M 58 Caucasian

69 Large cystic kidneys N 2 M 27 Caucasian, non-Hispanic

70 Renal cystic dysplasia, ectopic atrialtachycardia, CUA, seizures, LVH; dialy-sis from birth

Unknown 2 F <1 Caucasian

71 Steroid-resistant nephrotic syndrome N 4 F 8 Asian, multiracial72 MCD, unresponsive to steroids N 2 F 3 African/African-

American73 Glomerulocystic kidneys and

hepatoblastomaN 2 F 3 Hispanic or Latino

74 Alport syndrome 4 M 13 Caucasian75 Steroid-resistant nephrotic syndrome Y 4 M 4 Dominican Republic76 Gitelman syndrome N 3 F 23 Not provided77 Not provided Y 5 M 57 Not provided78 Nephronophthisis Y 2 F 38 Caucasian79 Premature newborn with severely en

larged cystic kidneys noted mid-trimes-ter, severe oligohydramnios, pulmonaryhypoplasia

N 2 F 0b Caucasian, Hispanic orLatino

80 Alport syndrome Unknown 4 F 11 Caucasian81 Hyponatremia, hypokalemia, nephrotic-

range proteinuria, glucosuriaN 3 M 1 Caucasian, non-

Hispanic82 Global glomerulosclerosis Y 4 F 65 African/African-


83 Juvenile nephronophthisis and MCKD Unknown 2 F 29 Not provided84 Not provided Unknown 5 M 14 Not provided85 X-linked hypophosphatemic rickets Unknown 3 F 1 Caucasian, non-

Hispanic86 Orofaciodigital syndrome I Unknown 2 F 21 Caucasian, non-

Hispanic87 Bilateral cystic kidneys Unknown 2 M 0b Native American,

Hispanic or Latino88 Renal tubular acidosis Unknown 1 F 9 Caucasian, Hispanic89 Childhood nephrotic syndrome, possibly

collapsing FSGSUnknown 4 F 9 African/African-


90 Alport syndrome N 4 F 6 Caucasian91 CKD, looking for APOL1 risk variants N 4 F 18 African/African-

American92 Bilateral cystic kidney disease Unknown 2 F 14 Caucasian, non-

Hispanic93 Congenital bilateral echogenic kidneys

with small cystsN 2 F 5 Not provided

94 Failure to thrive, presented with HTNand chronic renal failure

N 5 F 6 Caucasian

95 FSGS and hypertension Unknown 4 M 54 Not provided96 Alport syndrome, branchio-oto-renal

syndrome (BOR), ESRD,nephronophthisis

Unknown 2, 4 M 16 Caucasian

97 Bartter syndrome Unknown 3 F 2 Multiracial, Hispanicor Latino

98 Autosomal recessive polycystic kidneydisease

Unknown 2 M 0b Caucasian

99 Polycystic kidney disease Y 2 M 7 Caucasian100 Nephrotic syndrome N 4 M 2 Caucasian101 Chronic kidney stones and alkaline urine Unknown 2 M 18 Not provided102 Autosomal recessive polycystic kidney

diseaseUnknown 2 M 0b Brazilian/Mexican,

Hispanic or Latino103 Nephrotic-range proteinuria N 4 M <1 Caucasian

Continued


Dow



patients), Alport or Alport-like syndrome (10 patients), Bartter/Gitelman syndrome (9 patients) and ADPKD (7 patients)(Table 2). Age ranged from newborn to 81 years (0–6 years, 56patients; 7–14 years, 22 patients; 15–30 years, 26 patients;>30 years, 23 patients) (Table 3).

Variant identification and diagnostic rates in renalpatients

A genetic diagnosis was made in 54 patients (43%) (Table 4;46% solve rate between 0–14 years; 46% from 15–30 years and22% in those >30 years). By disease group, the solve rate was54% for CAKUT (7 of 13 patients), 53% for ciliopathies/tubu-lointerstitial diseases (17 of 32 patients), 45% for disorders oftubular transport (13 of 29 patients) and 33% for glomerulopa-thies (15 of 43 patients) (Figure 1 and Table 4). A number ofidentified variants were classified as VUSs as they did not meet

ACMG criteria for pathogenicity or likely pathogenicity(Tables 5–7).

D I S C U S S I O N

We identified a genetic basis for disease in 54 of 127 (44%)patients, demonstrating that broad-based genetic testing canaugment current clinical algorithms used to evaluate the renalpatient. The solve rate for cases decreased with age from 46%for patients between 0 and 14 years to 22% for patients>30 years old. Among solved cases, 9 were X-linked, 22 wereautosomal dominant and 22 were autosomal recessive (6 homo-zygous and 16 compound heterozygous variants). Family his-tory was positive in six autosomal dominant disorders (13unknown), four autosomal recessive disorders (14 unknown)and in one X-linked disorder (7 unknown). Pathogenic andlikely pathogenic variants included missense (32 of 75),

Table 3. Continued


104 Papillorenal syndrome (renal-colobomasyndrome)

N 1 M 2 Caucasian, Hispanic orLatino

105 Not provided N 5 M 14 Caucasian106 ADPKD N 2 M 12 Caucasian107 Congenital nephrotic syndrome Unknown 4 F 0b Hispanic or Latino108 Not provided Unknown 5 F 6 Not provided109 Isolated multicystic dysplastic kidney

disease and polycystic kidney diseaseUnknown 2 M 7 Not provided

110 NDI N 3 M 1 Caucasian, non-Hispanic

111 BOR or isolated CAKUT Unknown 1 F 2 Not provided112 Dent disease, Bartter or Gitelman

syndromesUnknown 3 M 23 Caucasian, non-

Hispanic113 ESRD of unknown etiology Y 5 M 20 Hispanic or Latino114 IgA nephropathy or FSGS N 4 M 11 African/African-

American115 FSGS or diffuse mesangial sclerosis Unknown 4 M 4 Caucasian116 Alport syndrome Y 4 M 13 Caucasian, non-

Hispanic117 Liddle syndrome Unknown 3 F 4 Not provided118 Nephrotic syndrome Unknown 4 M 8 African/African-

American119 CDK Stage 2, FSGS Unknown 4 F 16 African/African-


120 ESRD due to FSGS Unknown 4 F 20 Not provided121 Juvenile nephronophthisis Unknown 2 M <1 Not provided122 Zellweger syndrome, Galloway–Mowat

syndrome, podocytopathyUnknown 4 M 1 Caucasian, non-

Hispanic123 Steroid-resistant nephrotic syndrome Unknown 4 M <1 Caucasian, non-

Hispanic124 Bartter/Gitelman syndromes,

pseudohypoaldosteronism Type 1Unknown 3 M <1 African/African-

American125 Nephronophthisis Unknown 2 M 15 Caucasian126 Nephronophthisis N 2 F 12 Native Hawaiian or

other Pacific Islander,non-Hispanic

127 Bartter syndrome, Gitelman syndrome orNDI

Y 3 M 2 Caucasian, non-Hispanic

aDisease category is associated with indication for testing.bDisease categories: 1¼CAKUT; 2¼ ciliopathies or tubulointerstitial disease; 3¼ disorders of tubular ion transport; 4¼ glomerulopathies; 5¼ unclassified or other.ADTKD, autosomal dominant tubulointerstitial disease; ARPKD, autosomal recessive polycystic kidney disease; CUA, calcific uremic arteriolopathy; F, female; HTN, hypertension;LVH, left ventricular hypertrophy; M, male; MCD, minimal change disease; MCKD, medullary cystic kidney disease; TBM, thin basement membrane disease; U/S, ultrasound VSD,ventricular septal defect; Y/N, yes/no.


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thog

enic

)

68K

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yst

ones

,par

es-

thes

ias,

hype

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ciur

ia,

hypo

para

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oidi

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ESR

D

Y3

M58

1C

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NM

_000

388:

c.25

06G>

C,

p.V

al83

6Leu

het

Like

lypa

thog

enic

(PM

1,P

M2,

PP

2,P

P3)

Not

repo

rted

Hyp

ocal

cem

ia(A

D)

Thi

sm

anus

crip

t

69La

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cyst

icki

dney

sN

2M

271

PKD

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8311

G>

A,

p.G

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71Ly

s

het

Like

lypa

thog

enic

know

n(P

S1,P

M1,

PM

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Not

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rted

AD

PK

D[3

7]

70R

enal

cyst

icdy

spla

sia,

ecto

pic

atri

alta

chy-

card

ia,C

UA

,sei

zure

s,LV

H;d

ialy

sis

from

birt

h

Unk

now

n2

F<

11

WT

1N

M_0

0037

8:c.

1249

C>

T,

p.A

rg41

7Cys

het

Like

lypa

thog

enic

(PS1

,PM

2,P

P3)

Not

repo

rted

DD

S(A

D)

3[3

8]

79P

rem

atur

ene

wbo

rnw

ith

seve

rely

enla

rged

cyst

icki

dney

sno

ted

mid

-tri

mes

ter,

seve

reol

igoh

ydra

mni

os,p

ul-

mon

ary

hypo

plas

ia

N2

F<

11H

PKH

D1

NM

_138

694.

3:c.

9689

delA

,p.

Asp

3230

Val

fs*3

4

het

Pat

hoge

nic

know

n(P

VS1

,PM

2,P

P3,

PP

4)

0.03

9%LA

TA

RP

KD

[39]

NM

_138

694.

3:c.

6297

_630

0del

TG

,p.

Gln

2100

Gly

fs*7

het

Pat

hoge

nic

know

n(P

VS1

,PM

2,P

P3,

PP

4)

Not

repo

rted

[40]

80A

lpor

tsyn

drom

eU

nkno

wn

4F

111

CO

L4A

5N

M_0

0049

5:c.

1117

C>

T,

p.A

rg37

3*

het

Pat

hoge

nic

know

n(P

VS1

,PM

1,P

M2,

PP

3)

Not

repo

rted

Alp

orts

yndr

ome

(XLD

)[1

8]

84N

otpr

ovid

edU

nkno

wn

5M

14U

nkno

wn

NPH

P1W

hole

gene

dele

tion

hom

Pat

hoge

nic

know

n(P

VS1

,PS1

,PM

2)N

ephr

onop

hthi

sis

1(A

R)

2[4

1]

86O

rofa

ciod

igit

alsy

n-dr

ome

IU

nkno

wn

2F

211

OFD

1N

M_0

0361

1:c8

75_8

76de

lAT

,p.

Met

293G

lyfs

*15

het

Pat

hoge

nic

know

n(P

VS1

,PM

2,P

P3)

Not

repo

rted

Oro

faci

odig

ital

syn-

drom

eI

(AD

)[4

2]

87B

ilate

ralc

ysti

cki

dney

sU

nkno

wn

2M

<1

3HPK

HD

1he

tP

atho

geni

c(P

VS1

,P

M2,

PP

3)N

otre

port

edA

RP

KD

Thi

sm

anus

crip

t


Dow



NM

_138

694:

c.95

59de

lT,

p.Se

r318

7Leu

fs*3

3N

M_1

3869

4:c.

107C>

T,

p.T

hr36

Met

het

Like

lypa

thog

enic

know

n(P

S1,P

P3,

PP

5)

0.08

%N

FE[4

3]

90A

lpor

tsy

ndr

ome

N4

F6

1N

PH

S2N

M_0

1462

5:c.

871C

>T,

p.A

rg29

1Trp

het

Like

lypa

thog

enic

know

n(P

S1,P

M1,

PM

2,P

P2,

PP

3,P

P5)

0.02

9%E

ASt

eroi

d-re

sist

ant

ne-

phro

tic

syn

drom

e(A

R)

[44]

NM

_014

625:

c.68

6G>A

,p.

Arg

229G

ln

het

Like

lypa

thog

enic

whe

nin

heri

ted

wit

ha

path

ogen

ickn

own

(PS3

,PM

1,P

P2,

PP

3,P

P5)

6.98

%F

E[4

4]

93C

onge

nita

lbila

tera

lec

hoge

nic

kidn

eys

wit

hsm

allc

ysts

N2

F5

Unk

now

nH

NF1

BW

hole

gene

dele

tion

het

Pat

hoge

nic

know

n(P

VS1

,PM

2,P

P3)

HN

F1B

-rel

ated

neph

ropa

thy

[27]

94Fa

ilur

eto

thri

ve,p

re-

sen

ted

wit

hhy

pert

en-

sion

and

CK

D

N5

F6

1T

TC

21B

NM

_024

753:

c.15

161

2T>C

het

Pat

hoge

nic

(PV

S1,

PM

1,P

P3)

0.00

09%

NFE

Juve

nil

en

ephr

o-n

opht

hisi

s(A

R),

Jeu

ne

syn

drom

e(A

R),

orJo

ube

rtsy

n-

drom

e(A

R)

2T

his

man

usc

ript

NM

_024

753:

c.62

6C>T

,p.

Pro

209L

eu

het

Like

lypa

thog

enic

know

n(P

S3P

M2,

PP

3,P

P5)

0.03

%LA

T[4

5]

96A

lpor

tsyn

drom

e,br

anch

io-o

to-r

enal

synd

rom

e(B

OR

),E

SRD

,ne

phro

noph

this

is

Unk

now

n4

M16

1C

OL4

A5

NM

_000

495:

c.79

6C>

T,p

.Arg

266*

hem

iP

atho

geni

ckn

own

(PV

S1,P

M1,

PM

2,P

M4,

PP

3,P

P5)

Not

repo

rted

Alp

orts

yndr

ome

(XLD

)[4

6]

97B

artt

ersy

ndro

me

Unk

now

n3

F2

HK

CN

J1N

M_0

0022

0:c.

924C>

A,p

.Cys

308*

het

Pat

hoge

nic

(PV

S1,

PM

2,P

P3,

PP

5)N

otre

port

edB

artt

ersy

ndro

me

(AR

)T

his

man

uscr

ipt

NM

_000

220:

c.68

3G>

A,

p.G

ly22

8Glu

het

Like

lypa

thog

enic

know

n(P

S1,P

M2,

PP

3,P

P4)

0.00

18%

NFE

[47]

98A

utos

omal

rece

ssiv

epo

lycy

stic

kidn

eydi

seas

e

Unk

now

n2

M<

11

PKH

D1

NM

_138

694:

c.77

17C>

T,

p.A

rg25

73C

ys

het

Like

lypa

thog

enic

know

n(P

S1,P

M2,

PP

3,P

P4,

PP

5)

0.00

58%

EA

AR

PK

D[4

8]

NM

_138

694:

c.37

66de

lC,

p.G

ln12

56A

rgfs

*47

het

Pat

hoge

nic

know

n(P

VS1

,PS1

,PP

3)0.

12%

LAT

[48]

99P

olyc

ysti

cki

dney

dise

ase

Y2

M7

1PK

D1

NM

_000

296:

c.12

230_

1223

1del

AG

,p.

Glu

4077

Val

fs*7

8

het

Pat

hoge

nic

(PV

S1,

PM

2,P

P3)

Not

repo

rted

AD

PK

DT

his

man

uscr

ipt

103

Nep

hrot

icra

nge

prot

ein

uria

N4

M<1

1C

LCN

5N

M_0

0008

4:c.

1546

C>T

,p.

Arg

516T

rp

hem

iP

atho

gen

ickn

own

(PS1

,PS3

,PM

2,P

P2,

PP

3,P

P5)

Not

repo

rted

Den

tdi

seas

e3

[49]

104

Pap

illor

enal

synd

rom

e(r

enal

-col

obom

asy

ndro

me)

N1

M2

1HPA

X2

NM

_000

278:

c.69

delC

,p.

Val

26C

ysfs

X2

het

Pat

hoge

nic

know

n(P

VS1

,PM

2,P

P3,

PP

4,P

P5)

Not

repo

rted

Pap

illor

enal

synd

rom

e(A

D)

[50]

106

N2

M12

1PK

D1

het

0.02

7%N

FEA

DP

KD

[23]

Con

tinu

ed


Dow



Tab

le4.

Con

tin

ued

Cas

eIn

dica

tion

for

test

ing

Fam

ilyhi

stor

yD

isea

seca

tego

rya

Sex

Age

(yea

rs)

Rac

e/et

hnic

ity

Gen

eV

aria

ntZ

ygos

ity

AC

MG

clas

sific

atio

n[1

7]

MA

Fgn

omA

Db

Gen

etic

diag

nosi

s(A

D/A

R/X

LR)

Dis

ease

cate

gory

chan

gea

Firs

tre

port

ed

Aut

osom

aldo

min

ant

poly

cyst

icki

dney

dise

ase

NM

_000

296:

c.77

6G>

A,

p.C

ys25

9Tyr

Like

lypa

thog

enic

know

n(P

S1,P

M2,

PP

3,P

P5)

113

ESR

Dof

unkn

own

etio

logy

Y5

M20

HN

PH

P1

Who

lege

ne

dele

tion

hom

Pat

hoge

nic

know

n(P

VS1

,PS1

,PM

2)N

ephr

onop

hthi

sis

1(A

R)

2[4

1]

114

IgA

nep

hrop

athy

orFS

GS

N4

M11

2C

OL4

A4

NM

_000

092:

c.18

56G

>A,

p.G

ly61

9Asp

het

Like

lypa

thog

enic

know

n(P

S1,P

M2,

PP

3)

0.00

66%

AF

RA

lpor

tsy

ndr

ome

(AD

)[5

1]

115

FSG

Sor

diff

use

mes

angi

alsc

lero

sis

Unk

now

n4

M4

1W

T1

NM

_000

378:

c.13

33C>

T,

p.A

rg44

5Trp

het

Pat

hoge

nic

know

n(P

S1,P

S3,P

M2,

PP

3)N

otre

port

edD

DS

(AD

)[5

2]

116

Alp

orts

yndr

ome

Y4

M13

1C

OL4

A5

NM

_000

495:

c.12

26G>

A,

p.G

ly40

9Asp

het

Like

lypa

thog

enic

know

n(P

M1,

PM

2,P

P2,

PP

3,P

P5)

Not

repo

rted

Alp

ort

synd

rom

e(X

LD)

[18]

118

Nep

hrot

icsy

ndr

ome

Un

know

n4

M8

2A

PO

L1N

M_0

0113

6540

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1024

A>G

,p.

Ser3

42G

ly

hom

Ris

kal

lele

23%

AF

RD

ent

dise

ase

(XLR

)an

dA

PO

L1G

1/G

13

[53]

NM

_001

1365

40:

c.11

52T

>G,

p.Il

e384

Met

hom

Ris

kal

lele

22.9

%A

FR[5

3]

CLC

N5

NM

_000

084:

c.19

09C

>T,

p.A

rg63

7*

hem

iP

atho

gen

ickn

own

(PS1

,PV

S1,P

M2,

PP

3,P

P5)

Not

repo

rted

[54]

120

ESR

Ddu

eto

FSG

SU

nkno

wn

4F

20U

nkno

wn

PAX

2N

M_0

0027

8:c.

70_7

1ins

G,

p.V

al26

Gly

fx*2

8

het

Pat

hoge

nic

know

n(P

S1,P

VS1

,PM

1,P

M2,

PP

3,P

P5)

0.00

68%

AFR

FSG

S(A

D);

AP

OL1

G2/

G2

[55]

APO

L1N

M_0

0113

6540

:c.

1160

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5de

lAT

AA

TT

het

Ris

kal

lele

14.1

4%A

FR[5

3]

122

Zel

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Gal

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ay–M

owat

syn

drom

e,po

docy

topa

thy

Un

know

n4

M1

1O

CR

LN

M_0

0027

6:c.

1484

C>T

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Pro

495L

eu

hem

iP

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gen

ickn

own

(PS3

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1,P

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PP

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P3,

PP

5)

Not

repo

rted

Low

esy

ndr

ome

(XLR

)3

[56]

124

Bar

tter

/Git

elm

ansy

n-dr

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udoh

y-po

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ster

onis

mty

pe1

Unk

now

n3

M<

12

NR

3C2

NM

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901:

c.10

02_1

003i

nsG

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p.Se

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Val

fs*4

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Pat

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(PV

S1,

PM

2,P

P3)

Not

repo

rted

Pse

udoh

ypoa

ldos

tero

-ni

smI

(AD

)T

his

man

uscr

ipt

125

Nep

hron

opht

hisi

sU

nkno

wn

2M

151

NPH

P1W

hole

gene

dele

tion

hom

Pat

hoge

nic

know

n(P

VS1

,PS1

,PM

2)N

ephr

onop

hthi

sis

1(A

R)

[41]

126

Nep

hron

opht

hisi

sN

2F

125

NPH

P1W

hole

gene

dele

tion

hom

Pat

hoge

nic

know

n(P

VS1

,PS1

,PM

2)N

ephr

onop

hthi

sis

1(A

R)

[41]

Pat

ient

sin

who

mth

ege

neti

cdi

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chan

ged

the

clin

ical

diag

nosi

sar

esh

own

inbo

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nt.

a Dis

ease

cate

gory

:1¼

CA

KU

T;2¼

cilio

path

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rsti

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Dow



nonsense (9 of 75), canonical splice site variants (4 of 75), smallindels (17 of 75) and large CNVs (10 of 75), demonstrating thepower to detect all types of genetic variants (Figure 1).

In 41 of 54 patients with a genetic diagnosis, data confirmedthe clinical impression (i.e. ADPKD as ADPKD, Bartter asBartter, etc.) but also provided prognostic information, guidedclinical management and/or enabled counseling (Figure 1 andTable 4). For example, the identification of a truncating variantin PKD1 (NM_000296: c.12230_12231delAG) in a 7-year-oldchild with polycystic kidney disease (Case 99) mandates regularevaluation for increasing kidney volume, since truncatingPKD1 variants predict a median onset of end-stage renal disease(ESRD) at 55 years of age, substantially earlier than non-truncating PKD1 variants or any PKD2 variant [72]. In anotherexample, the diagnosis of CKD at age 10 years (Case 8) in twofraternal twins born prematurely led to a clinical suspicion ofjuvenile nephronophthisis. We identified two null variants inRPGRIP1L, which is reported in the allelic disorders Joubertsyndrome, COACH syndrome and Meckel syndrome. Patientswith hypomorphic RPGRIP1L variants develop Joubert syn-drome or COACH syndrome (Joubert features with congenitalhepatic fibrosis), while those with null variants develop Meckelsyndrome, which is considered to be at the more severe end ofthe clinical disease spectrum [73]. While the phenotype can bevariable with Joubert and COACH syndrome, awareness of thetype of genetic variants should prompt a careful and guidedevaluation for extrarenal features, such as liver disease, that mayrequire treatment.

In the remaining 13 cases (24%), genetic testing changed theclinical diagnosis, helped to direct future care, guided genetic

counseling, and/or directed the evaluation process for living do-nor candidates. For example, the indication for screening in a1-month-old (Case 26) was bilateral hypoplastic dysplastic kid-neys. Upon testing, a null variant was identified in EYA1, con-sistent with the diagnosis of branchio-oto-renal syndrome 1(BOR1). BOR1 exhibits variable penetrance and is character-ized by hearing loss, branchial defects, preauricular pits andCAKUT [74]. On further evaluation, the child was found tohave hearing loss and preauricular pits.

We also identified bilineal autosomal dominant diseasesand digenic autosomal recessive disease. As an example ofthe former, in a 6-year-old female (Case 1) with bilateral mul-ticystic dysplastic kidneys, pathogenic variants were identi-fied in both PKD1 (a single nucleotide deletion) and PKD2 (anucleotide substitution that converts the start codon to ly-sine). Each of these variants alone is sufficient to causeADPKD, and the co-inheritance in this patient is consistentwith her severe and atypical phenotype. Bilineal disease israre in humans, although it has been noted in experimentalmice [75–77].

In one case (Case 70), a medically actionable variant in WT1was incidentally identified in a 6-month-old infant with renalcystic dysplasia, ESRD, ectopic atrial tachycardia, left ventricu-lar hypertrophy and seizures. The variant, p.Arg417Cys, isultra-rare, predicted pathogenic and previously reported in twopatients—one with Denys–Drash syndrome (DDS) and Wilms’tumor and one child with DDS who died shortly after birth [38,78]. In light of these reports, the variant was reported to the cli-nician as likely pathogenic for DDS with the attendant risks ofWilms’ tumor.

Positivediagnosis

Change indiagnosis

Number of pathogenic variants

Disease categoryNumber of genes

KidneySeq solve rate 43%, 54 of 127

KidneySeq panel177 genes

127 renalpatients

Tubulartransport

49

CAKUT29

Ciliopathy/tubulo-interstitial

58

Glomerulopathy42

Unclassified9

45%13 of 29

54%7 of 13

53%17 of 32

33%14 of 43

30%3 of 10

7%2 of 29

23%3 of 13

3%1 of 32

9%4 of 43

20%2 of 10

Nonsense8

Canonicalsplice 4

Large CNV10

Small indel16

Missense32

Positives41

Change indiagnosis 13

Negatives74

FIGURE 1: Outcome of KidneySeq panel testing in 127 renal patients. The positive diagnosis rate in each disease category is showntogether with the percentage where diagnosis changed. A pie chart shows the number and types of pathogenic variants and the overallsolve rate.


Dow



Tab

le5.

VU

Ss

Cas

eIn

dica

tion

for

test

ing

Fam

ilyhi

stor

yD

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seca

tego

rya

Sex

Age

(yea

rs)

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nici

tyG

ene

Var

iant

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ybA

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ficat

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rule

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7]

MA

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port

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Pos

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rote

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ia,F

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M_0

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p.A

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PM

2,P

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ith

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nect

inde

posi

ts(A

D)

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das

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ated

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mia

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p.Il

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p.G

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sm

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AT

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man

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102:

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man

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ipt

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ipt

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292:

c.52

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A,

p.A

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man

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man

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p.Se

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p.A

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2720

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p.Il

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ipt

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AFR

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Con

tinu

ed


Dow



Tab

le5.

Con

tin

ued

Cas

eIn

dica

tion

for

test

ing

Fam

ilyhi

stor

yD

isea

seca

tego

rya

Sex

Age

(yea

rs)

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nici

tyG

ene

Var

iant

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ocit

ybA

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assi

ficat

ion/

rule

s[1

7]

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nom

adc

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tre

port

edby

Pos

sibl

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d

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oid-

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stan

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phro

tic

synd

rom

eD

omin

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Rep

ublic

NM

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428:

c.16

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G,

p.Il

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Val

76G

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man

synd

rom

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otpr

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edEY

A1

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503:

c.40

3G>

A,

p.G

ly13

5Ser

het

PP

30.

064%

EA

Clin

Var

N

77N

otpr

ovid

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5M

57N

otpr

ovid

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M_0

0109

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688G>

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p.A

rg56

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PM

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FEC

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ephr

onop

hthi

sis

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casi

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_032

575:

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p.A

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Ser

het

BP

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0.09

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FT

his

man

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ipt

N

TR

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621:

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A,

p.A

la34

4Thr

het

PM

2N

otre

port

edT

his

man

uscr

ipt

N

82G

loba

lglo

mer

ulos

cler

osis

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F65

Afr

ican

/Afr

ican

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mer

ican

CO

L4A

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0009

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3143

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port

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his

man

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83Ju

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lene

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ase

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prov

ided

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3N

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0033

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1967

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het

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FET

his

man

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ipt

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ked

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phat

emic

rick

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now

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Cau

casi

an,n

on-

His

pani

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OG

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413:

c.70

0þ

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The

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208%

NFE

Clin

Var

N

88R

enal

tubu

lar

acid

osis

Unk

now

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Cau

casi

an,

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pani

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His

het

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ibly

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now

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ican

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ican

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mer

ican

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M_0

0029

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G>

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p.V

al19

56M

ethe

t–

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FET

his

man

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ipt

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90A

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drom

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sian

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NM

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1263

35:c

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A,

p.A

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het

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het

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4]N

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ilate

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141

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0029

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p.T

yr29

91A

sphe

tP

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P3

Not

repo

rted

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sm

anus

crip

tY

93C

onge

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tera

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ith

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p.T

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het

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102

Aut

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cys-

tic

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nkno

wn

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razi

lian/

Mex

ican

His

pani

cH

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AN

M_0

0045

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1133

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p.Se

r378

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het

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port

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his

man

uscr

ipt

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107

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geni

taln

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otic

synd

rom

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wn

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CO

L4A

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G>

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p.G

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6Lys

het

PM

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P2,

PP

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0058

%E

AT

his

man

uscr

ipt

N

108

Not

prov

ided

Unk

now

n5

F6

Not

prov

ided

IFT

140

NM

_014

714:

c.88

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ided

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0.91

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Dow



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man

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ipt

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112

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p.Le

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het

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22%

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N

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28G>

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p.A

rg43

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0.00

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man

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sm

anus

crip

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114

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thy

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ican

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ican

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8:c.

1178

G>

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p.A

rg39

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PM

2,P

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sm

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121

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p.Il

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het

PM

2,P

P3

0.00

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NM

_153

240:

c.46

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C,

p.A

la15

4Pro

het

PM

2,P

P3

Not

repo

rted

Clin

Var

Y

123

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oid-

resi

stan

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tic

synd

rom

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PP

50.

001%

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Var

(lik

ely

path

ogen

ic)

Y

125

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hron

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hisi

sU

nkno

wn

2M

15C

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sian

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NM

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901:

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1G>

A,

p.A

rg24

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het

0.00

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FET

his

man

uscr

ipt

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SIX

2N

M_0

1693

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p.P

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6]N

127

Bar

tter

synd

rom

e,G

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rom

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ispa

nic

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Full

gene

dele

tion

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LP*

(PV

S1,P

M2)

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9N

M_0

0112

6335

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44G>

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la18

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het

PP

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PP

50.

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N

a Dis

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hth

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ozyg

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hem

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miz

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s.c gn

omA

D:h

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ican

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sian

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sh);

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A¼

Sout

hA

sian

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es(Y

),no

(N)

orun

know

n(U

).e N

ewbo

rn.

Jew

ish#

No

gnom

AD

data

.M

,mal

e;F,

fem

ale.

HT

N,h

yper

tens

ion;

VSD

,ven

tric

ular

sept

alde

fect

;CU

A,c

alci

ficur

emic

arte

riol

opat

hy.

New

born

.


Dow



Tab

le6.

Ris

kal

lele

s

Cas

eIn

dica

tion

for

test

ing

Fam

ilyhi

stor

yD

isea

seca

tego

ryaSe

xA

ge(y

ear)

Eth

nici

tyG

ene

Var

iant

Zyg

ocit

ybA

CM

Gcl

assi

ficat

ion/

rule

s[1

7]

MA

Fgn

omA

Dc

Ass

ocia

ted

dise

ase

Firs

tre

port

edby

9FS

GS

Unk

now

n4

M54

Afr

ican

/Afr

ican

-A

mer

ican

APO

L1N

M_0

0113

6540

:c.

1024

A>

G,p

.Ser

342G

lyho

mR

isk

alle

le23

%A

FRFS

GS,

hype

rten

sive

neph

rosc

lero

sis

and

HIV

asso

ciat

edne

phro

path

y

[53]

G1/

G1

NM

_001

1365

40:

c.11

52T>

G,p

.Ile3

84M

etR

isk

alle

le22

.9%

AFR

[53]

15H

yper

calc

emia

,hyp

ocal

-ci

uria

.Sus

pici

onof

CaS

Rin

acti

vati

ngm

utat

ion

N3

F81

Cau

casi

anC

aSR

NM

_000

388:

c.29

56G>

T,

p.A

la98

6Ser

het

PM

2,P

P2,

BP

6N

otre

port

edH

yper

calc

emia

[67]

46FS

GS

orm

inim

alch

ange

dise

ase.

Per

sist

ent

prot

einu

ria

Unk

now

n4

M5

Cau

casi

an,n

on-

His

pani

cPL

CG

2N

M_0

0266

1:c.

3563

C>

T,

p.P

ro11

88Le

uhe

t0.

0067

%N

FESt

eroi

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nsit

ive

ne-

phro

tic

synd

rom

eT

his

man

uscr

ipt

72M

CD

,unr

espo

nsiv

eto

ster

oids

N2

F3

Afr

ican

/Afr

ican

-A

mer

ican

APO

L1N

M_0

0113

6540

:c.

1024

A>

G,p

.Ser

342G

lyhe

tR

isk

alle

le23

%A

FRFS

GS,

hype

rten

sive

neph

rosc

lero

sis

and

HIV

asso

ciat

edne

phro

path

y

[53]

G1/

G2

NM

_001

1365

40:

c.11

52T>

G,p

.Ile3

84M

ethe

tR

isk

alle

le22

.9%

AFR

[53]

NM

_001

1365

40:

c.11

60_1

165d

elA

TA

AT

T,

p.A

sn38

8_T

yr38

9del

het

Ris

kal

lele

14.1

4%A

FR[5

3]

101

Chr

onic

kidn

eyst

ones

and

alka

line

urin

eU

nkno

wn

3M

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otpr

ovid

edA

TP6

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M_0

0169

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298G>

A,

p.A

sp10

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het

PP

2,P

P3

0.16

%E

AK

idne

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ones

Thi

sm

anus

crip

t11

8N

ephr

otic

synd

rom

eU

nkno

wn

4M

8A

fric

an/A

fric

an-

Am

eric

anA

POL1

NM

_001

1365

40:

c.10

24A>

G,p

.Ser

342G

lyho

mR

isk

alle

le23

%A

FRFS

GS,

hype

rten

sive

neph

rosc

lero

sis

and

HIV

asso

ciat

edne

phro

path

y

[53]

G1/

G1

NM

_001

1365

40:

c.11

52T>

G,p

.Ile3

84M

etR

isk

alle

le22

.9%

AFR

[53]

119

CD

KSt

age

2,FS

GS

Unk

now

n4

F16

Afr

ican

/Afr

ican

-A

mer

ican

APO

L1N

M_0

0113

6540

:c.

1024

A>

G,p

.Ser

342G

lyho

mR

isk

alle

le23

%A

FRFS

GS,

hype

rten

sive

neph

rosc

lero

sis

and

HIV

asso

ciat

edne

phro

path

y

[53]

G1/

G1

NM

_001

1365

40:

c.11

52T>

G,p

.Ile3

84M

etR

isk

alle

le22

.9%

AFR

[53]

120

ESR

Ddu

eto

FSG

SU

nkno

wn

4F

20N

otpr

ovid

edA

POL1

G2/

G2N

M_0

0113

6540

:c.

1160

_116

5del

AT

AA

TT

,p.

Asn

388_

Tyr

389d

el

hom

Ris

kal

lele

14.1

4%A

FRFS

GS,

hype

rten

sive

neph

rosc

lero

sis

and

HIV

asso

ciat

edne

phro

path

y

[53]

a Dis

ease

cate

gory

isas

soci

ated

wit

hth

ein

dica

tion

for

test

ing.

1¼

CA

KU

T;2¼

Cili

opat

hies

ortu

bulo

inte

rsti

tial

dise

ase;

3¼

Dis

orde

rsof

tubu

lar

ion

tran

spor

t;4¼

Glo

mer

ulop

athi

es;5¼

Unc

lass

ified

orO

ther

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ygos

ity:

het,

hete

rozy

gous

;hom

,hom

ozyg

ous;

hem

i,he

miz

igou

s.c gn

omA

D:h

ighe

stm

inor

alle

lefr

eque

ncy

repo

rted

.AFR

,Afr

ican

;EA

,Eas

tA

sian

;NFE

,Eur

opea

n(n

on-F

inni

sh).

Jew

ish#

No

gnom

AD

data

.N

,no;

M,m

ale;

F,fe

mal

e.


Dow



Tab

le7.

Pat

hoge

nic

carr

iers

Cas

eIn

dica

tion

for

test

ing

Fam

ilyhi

stor

yD

isea

seca

tego

rya

Sex

Age

(yea

rs)

Eth

nici

tyG

ene

Var

iant

Zyg

ocit

ybA

CM

Gcl

assi

fica-

tion

/rul

es[1

7]M

AF

gnom

AD

cR

epor

ted

inA

ssoc

iate

ddi

seas

e

75St

eroi

d-re

sist

ant

ne-

phro

tic

synd

rom

eY

4M

4D

omin

ican

Rep

ublic

BB

S1D

elet

ion

chr1

1:66

2781

19-6

6301

084

het

Thi

sm

anus

crip

tB

BS

carr

ier

83Ju

veni

lene

phro

noph

-th

isis

and

med

ulla

rycy

stic

kidn

eydi

seas

e

Y2

F29

Not

prov

ided

SLC

12A

3N

M_0

0033

9:c.

1967

C>

T,

p.P

ro65

6Leu

het

PP

2,P

P3

0.02

1%N

FE[6

8]G

itel

man

carr

ier

85X

-lin

ked

hypo

phos

-ph

atem

icri

cket

sU

nkno

wn

3F

1C

auca

sian

,non

-H

ispa

nic

HO

GA

1N

M_1

3841

3:c.

700þ

5G>

The

tP

P2,

PP

50.

21%

NFE

[69]

Pri

mar

yhy

pero

xa-

luri

aII

Ica

rrie

r88

Ren

altu

bula

rac

idos

isU

nkno

wn

1F

9C

auca

sian

,His

pani

cIF

T14

0N

M_0

1471

4:c.

1541

T>

A,

p.Le

u514

His

het

PP

3,B

P6

1.58

%FE

[70]

Jeun

esy

ndro

me

carr

ier

108

Not

prov

ided

Unk

now

n5

F6

Not

prov

ided

SLC

12A

1N

M_0

0033

8:c.

1872

delC

het

Pat

hoge

nic

(PV

S1,

PM

2,P

P3)

0.03

2%SA

Thi

sm

anus

crip

tB

artt

ersy

ndro

me

1ca

rrie

r11

1B

ranc

hio-

oto-

rena

lsy

ndro

me

oris

olat

edC

AK

UT

Unk

now

n1

F2

Not

prov

ided

FGF2

3N

M_0

2063

8:c.

59de

lG,

p.Se

r20T

hrfs

*20

het

LP*

(PV

S1,P

M2)

Not

repo

rted

Thi

sm

anus

crip

tN

112

Den

tdis

ease

,Bar

tter

orG

itel

man

synd

rom

es

Unk

now

n3

M23

Cau

casi

an,n

on-

His

pani

cA

TP7

BN

M_0

0005

3:c.

2972

C>

T,

p.T

hr99

1Met

het

Like

lypa

thog

enic

PS3

,PM

1,P

P2,

PP

3,P

P5

0.24

%N

FE[7

1]W

ilson

dise

ase

carr

ier

a Dis

ease

cate

gory

isas

soci

ated

wit

hth

ein

dica

tion

for

test

ing.

1¼

CA

KU

T;2¼

Cili

opat

hies

ortu

bulo

inte

rsti

tial

dise

ase;

3¼

Dis

orde

rsof

tubu

lar

ion

tran

spor

t;4¼

Glo

mer

ulop

athi

es;5¼

Unc

lass

ified

orO

ther

.bZ

ygos

ity:

het,

hete

rozy

gous

;hom

,hom

ozyg

ous;

hem

i,he

miz

igou

s.c gn

omA

D:h

ighe

stm

inor

alle

lefr

eque

ncy

repo

rted

.FE

,Eur

opea

nFi

nnis

h;N

FE,E

urop

ean

(non

-Fin

nish

);SA

,Sou

thA

sian

.Je

wis

h#N

ogn

omA

Dda

ta.

Y,y

es;M

,mal

e;F,

fem

ale.


Dow



In some cases, identified variants had insufficient evidenceto be labeled as likely pathogenic or pathogenic and werereported as VUSs (Tables 5–7). In two cases, the genetic var-iants did not meet strict ACMG criteria for likely pathogenicityand were labeled as VUSs, but in the clinical context, the multi-disciplinary group considered these as probably causal(Tables 5–7, Cases 57 and 92). In two other cases, variants clas-sified as likely pathogenic by ACMG criteria were reported asVUSs because the genetic disease appeared irrelevant to theclinical phenotype. One of these was a case with nephrogenicdiabetes insipidus (NDI) and nephrocalcinosis with hypophos-phatemia (Tables 5–7, Case 44), where an identified variant inKAL1 was classified as likely pathogenic for Kallmann syn-drome by ACMG criteria. In the other, a case with hypomagne-semia and dilated cardiomyopathy (Tables 5–7, Case 16), alikely pathogenic variant in ROBO2 for CAKUT was identifiedbut reported as a VUS. In other instances, we identified allelesthat increase risk for specific renal diseases (Tables 5–7). Fivepatients with FSGS, nephrotic syndrome or CKD were homozy-gous or compound heterozygous for variants in APOL1 thatsubstantially increase the risk for FSGS in Americans of sub-Saharan African descent [79, 80]. Other risk variants were iden-tified in CaSR, PLCG2 and ATP6V1B1, which increase the riskof hypercalcemia, steroid-sensitive nephrotic syndrome andkidney stones, respectively [81–83].

CNVs are significant contributors to genetic renal diseaseand their detection was an important component of our analy-sis [84]. We identified pathogenic CNVs in 18% of positive di-agnoses, including four cases of autosomal recessive JN1(NPHP1), two cases of autosomal dominant CAKUT (HNF1B),one case each of autosomal recessive Alport syndrome(COL4A4) and autosomal recessive pseudohypoaldosteronism(SCNN1B) and a possible tri-allelic form of Gitelman syndrome(CLCNKB; Figure 2).

Alternative methods to provide comprehensive unbiasedscreening for genetic renal disorders include genome sequenc-ing (GS) and/or ES, both of which have been used to diagnosemonogenic renal disorders in a research setting and have beenused in the clinical setting when locus heterogeneity is extreme,the phenotype is very indistinct, or the renal features are only aminor part of a multisystem disease [85, 86]. Neither GS nor ESis optimized for the renal exome, which includes challengingregions like the first 32 exons of PKD1, which are duplicated assix pseudogenes on chromosome 16. Nevertheless, ES remainsan alternative as described by Lata et al., who report a 24%

diagnostic rate in a selected population of adults with CKD, ex-cluding ADPKD, where a genetic disease was suspected basedon family history or there was early age-of-onset of disease [10].In another study of a larger cohort of patients with CKD, ESidentified diagnostic variants in 9.3% of patients [12].

There are some limitations and caveats to our testing strat-egy. First, as in ES, some types of genetic variants that occurwithin tandem oligonucleotide repeats, such as the cytosine in-sertion within a cytosine repeat sequence in MUC1, are difficultto identify [87]. Second, new genetic causes of kidney diseasecontinue to be identified that may not have been present on thediagnostic gene panel at the time of testing. Included in this cat-egory are new and rare causes of kidney disease such asDZIP1L, FAT1 and the NUP and IFT family genes. Third, wewere not always able to verify the presence of variants in transto confirm compound heterozygosity for autosomal recessivedisorders due to lack of parent or offspring samples. In addi-tion, we purposefully omitted complement genes on this panelbecause we have developed a discrete panel for ultra-rarecomplementopathies, including atypical hemolytic uremic syn-drome and C3 glomerulopathy. Finally, it should be noted thatour diagnostic yield is high and warrants confirmation withlarger studies.

In summary, these data add to the body of literature sug-gesting that genetic renal diseases are underdiagnosed andunderappreciated in both children and adults [10, 88–90]. Inthis cohort of patients, presumably selected by cliniciansbased on suspicion of monogenic kidney disease, the geneticdiagnostic rate is very high and is likely to be lower if moreindiscriminate patient testing becomes the norm.Nevertheless, panels facilitate identification of a broad rangeof Mendelian diseases, including cystic kidney disease, theCAKUTs, tubulointerstitial disease and glomerular disease, aswell as non-Mendelian genetic disease, bilineal and digenic dis-ease, atypical forms of disease and unsuspected disease. As such,comprehensive genetic testing has an important place in the eval-uation and care of the renal patient [91].

S U P P L E M E N T A R Y D A T A

Supplementary data are available at ndt online.

A U T H O R S ’ C O N T R I B U T I O N S

M.A.M., C.P.T. and R.J.S. conceived the study and wrote themanuscript; M.A.M. conducted genetic testing; R.R.S.

3.0

2.0

1.0

0R

atio

227900000 227950000Position

COL4A4

228000000

FIGURE 2: CNV identified in Case 33. The ratio of expected-to-observed sequence reads shows �50% reduction in signal, which is consistentwith heterozygous deletion of exons 10–40 in COL4A4.


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performed bioinformatic analysis; M.E.F., C.A.C., R.J.S. andC.P.T. interpreted genetic test results with contributions fromC.J.N., A.E.K. and M.J.K. All authors approved the final versionof the manuscript.

C O N F L I C T O F I N T E R E S T S T A T E M E N T

None declared.

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Received: 18.3.2019; Editorial decision: 23.7.2019


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