Supplementary Table 1a: 41 that represent monogenic causes of human isolated CAKUT, if mutated (Note that underlined indicates that we identified a variant in this gene as the causative mutation in this cohort) Mode of Gene Reference Inheritenance ACE I-converting enzyme Gribouval Nat Genet 37:964, 2005 AR AGT Angiotensinogen Gribouval Nat Genet 37:964, 2005 AR AGTR1 Angiotensin II receptor, type 1 Gribouval Nat Genet 37:964, 2005 AR CHRM3 Muscarinic acetylcholine receptor M3 Weber AJHG 19:634, 2011 AR ETV4 ETS translocation variant 4, E1A enhancer binding protein Chen IJPCH 4:61, 2016 AR FRAS1 Extracellular matrix protein FRAS1 Kohl JASN 25:1917, 2014 AR FREM1 FRAS1 related extracellular matrix protein 1 Kohl JASN 25:1917, 2014 AR FREM2 FRAS1 related extracellular matrix protein 2 Kohl JASN 25:1917, 2014 AR GRIP1 Glutamate receptor interacting protein 1 Kohl JASN 25:1917, 2014 AR HPSE2 Heparanase 2 (Inactive) Bulum Nephron 130:54, 2015 AR ITGA8 Integrin α8 Humbert AJHG 189:1260, 2014 AR -rich repeats-and immunoglobulin-like domains-containing LRIG2 Stuart AJHG 92:259, 2013 AR protein 2 REN Gribouval Nat Genet 37:964, 2005 AR Heat-shock protein 75 (also known as TNF receptor-associated protein TRAP1 Saisawat KI 85:880, 2014 AR 1) FGF20 Fibroblast Growth Factor 20 Barak Dev Cell 22:1191, 2012 AR BMP4 Bone morphogenic protein 4 Weber JASN 19:891, 2008 AD CHD1L Chromodomain helicase DNA binding protein 1-like Brockschmidt NDT 27:2355, 2012 AD CRKL CRK Like Proto-Oncogene, adaptor protein Lopez-Rivera NEJM 376:742, 2017 AD DSTYK Dual serine/threonine and tyrosine protein kinase Sanna-Cherchi NEJM 369:621, 2013 AD EYA1 Eyes absent homolog 1 Abdelhak Nat Genet 15:157, 1997 AD Pandolfi Nat Genet 11:40, 1995; Van Esch GATA3 GATA binding protein 3 AD Nature 406:419, 2000 GREB1L Growth regulation by estrogen in breast cancer 1-like Brophy Genetics 207:215, 2017 AD HNF1B HNF homeobox B Lindner Hum Mol Genet 24:263, 1999 AD MUC1 Mucin 1 Kirby Nat Genet 45:299, 2013 AD NRIP1 Nuclear receptor interacting protein 1 Vivante JASN 2017 28:2364, 2017 AD PAX2 Paired box 2 Sanyanusin Hum Mol Genet 4:2183, 1995 AD PBX1 PBX homeobox 1 Heidet JASN 28:2901, 2017 AD RET Proto-oncogene tyrosine-protein kinase receptor Ret Skinner AJHG 82:344, 2008 AD Hwang Hum Genet 134:905, 2015; Lu AJHG ROBO2 Roundabout, axon guidance receptor, homolog 2 (Drosophila ) AD 80:616, 2007 SALL1 Sal-like protein 1 (also known as spalt-like transcription factor 1) Kohlhase Nat Genet 18:81, 1998 AD SIX1 SIX homeobox 1 Ruf Proc. Nat. Acad. Sci. 101: 8090, 2004 AD SIX2 SIX homeobox 2 Weber JASN 19:891, 2008 AD SIX5 SIX homeobox 5 Hoskins AJHG 80:800, 2007 AD SLIT2 Slit homolog 2 Hwang Hum Genet 134:905, 2015 AD SOX17 Transcription factor SIX-17 Gimelli Hum Mut 31:1352, 2010 AD SRGAP1 SLIT-ROBO Rho GTPase activating protein 1 Hwang Hum Genet 134:905, 2015 AD TBX18 T-Box transcription factor Vivante AJHG 97:291, 2015 AD TNXB Tenascin XB Gbadegesin JASN 24:1313, 2013 AD UPK3A Uroplakin 3A Jenkins JASN 16:2141, 2005 AD Biason-Lauber NEJM 351:792, 2004; Mandel WNT4 Protein Wnt-4 AD AJHG 82:39, 2008; Vivante JASN 24:550, 2013 KAL1 Anosmin 1 Hardelin PNAS 89:8190, 1992 XL AR, autosomal recessive; AD, autosomal dominant; XL; X-linked. Supplementary Table 1b: 50 genes that represent monogenic causes of human nephrotic syndrome, if mutated (Note that underlined gene indicates that we identified a variant in this gene as the causative mutation in this cohort) Mode of Gene Protein Reference Inheritenance ADCK4 AarF domain containing kinase 4 Ashraf J Clin Invest 123:5179, 2013 AR ALG1 ALG1, Chitobiosyldiphosphodolichol Beta-Mannosyltransferase Harshman Pediatr Int 58:785, 2016 AR ARHGDIA Rho GDP dissociation inhibitor (GDI) alpha Gee J Clin Invest 123:3243, 2013 AR AVIL Advillin Rao J Clin Invest 127:4257, 2017 AR CD2AP CD2 associated protein Kim Science 300:1298, 2003 AR COQ2 Coenzyme Q2 4-hydroxybenzoate polyprenyltransferase Diomedi-Camassei JASN 18:2773, 2007 AR COQ6 Coenzyme Q6 monooxygenase Heeringa J Clin Invest 121:2013, 2011 AR CRB2 Crumbs, Drosphilia, Homolog of 2 Ebarasi AJHG 96: 153-161, 2015 AR CUBN Cubilin (intrinsic factor-cobalamin receptor) Ovunc JASN 22:1815, 2011 AR DGKE Diacylglycerol kinase epsilon Lemaire Nat Genet 45: 531, 2013 AR EMP2 Epithelial membrane protein 2 Gee AJHG 94:884, 2014 AR FAT1 Fat tumor suppressor, drosphila, homolog of, 1 Gee Nat Commun 7:10822, 2016 AR ITGA3 Integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) Yalcin Hum Mol Genet 24:3679, 2015 AR ITGB4 Integrin, beta 4 Kambham AJKD 36:190, 2000 AR KANK1 KN motif and ankyrin repeat domain-containing protein 1 Gee J Clin Invest 125:2375, 2015 AR KANK2 KN motif and ankyrin repeat domain-containing protein 2 Gee J Clin Invest 125:2375, 2015 AR KANK4 KN motif and ankyrin repeat domain-containing protein 3 Gee J Clin Invest 125:2375, 2015 AR LAGE3 L antigen family member 3 Braun Nat Genet 49:1529, 2017 AR LAMB2 Laminin, beta 2 Zenker Hum Mol Genet 12:2625, 2004 AR LCAT Lecithin-Cholesterol Acyltransferase Taramelli Hum Genet 85:195, 1990 AR Membrane-associated guanylate kinase, WW and PDZ domains- MAGI2 Bierzynska JASN 28:1614, 2017 AR containing 2 MYO1E Homo sapiens myosin IE (MYO1E) Mele NEJM 365:295, 2011 AR NPHS1 Nephrin Kestila Mol Cell 1:575, 1998 AR NPHS2 Podocin Boute Nat Genet 24:349, 2000 AR NUP107 Nucleoporin, 107-KD Miyake AJHG 97:555, 2015 AR NUP133 Nucleoporin 133-KD Braun Nat Genet 48:457, 2016 AR NUP205 Nucleoporin, 205-KD Braun Nat Genet 48:457, 2016 AR NUP85 Nucleoporin 85-KD Braun Nat Genet 48:457, 2016 AR NUP93 Nucleoporin, 93-KD Braun Nat Genet 48:457, 2016 AR OSGEP O-sialoglycoprotein endopeptidase Braun Nat Genet 48:457, 2016 AR PDSS2 Prenyl (decaprenyl) diphosphate synthase, subunit 2 Lopez AJHG 79:1125, 2006 AR PLCE1 Phospholipase C, epsilon 1 Hinkes Nat Genet 38:1397, 2006 AR PTPRO Protein tyrosine phosphatase, receptor type, O Ozaltin AJHG 89:139, 2011 AR SCARB2 Scavenger receptor class B, member 2 Badhwar Brain 127: 2173, 2004 AR SGPL1 Sphingosine 1 phosphate lyase 1 Lovric J Clin Invest 127: 912, 2017 AR SWI/SNF related, matrix associated, actin dependent regulator SMARCAL1 Boerkoel Nat Genet 30:215, 2002 AR of chromatin, subfamily a-like 1 TP53RK TP53-regulating kinase Braun Nat Genet 49:1529, 2017 AR TPRKB TP53RK binding protein Braun Nat Genet 49:1529, 2017 AR WDR73 WD repeat-containing protein 73 Colin AJHG 95:637, 2014 AR XPO5 Exportin 5 Braun Nat Genet 48:457, 2016 AR ACTN4 Actinin, alpha 4 Kaplan Nat Genet 24(3):251, 2000 AD ANLN Actin-binding protein anillin Gbadegesin JASN 25:1991, 2014 AD ARHGAP24 Rho GTPase activating protein 24 Akilesh J Clin Invest 121:4127, 2011 AD INF2 Inverted formin, FH2 and WH2 domain containing Brown Nat Genet 42:72, 2010 AD LMX1B LIM Homeobox Transcription Factor 1 Beta Dreyer Nat Genet 19:47 1998 AD MYH9 Myoson heavy chain 9, nonmuscle Heath AJHG 69:1033, 2001 AD TRPC6 Transient receptor potential cation channel, subfamily C, member 6 Winn Science 308:1801, 2005 AD WT1 Wilms Tumor 1 Melo J Clin Endocrinol Metab 87:2500, 2002 AD NXF5 Nuclear RNA export factor 5 Esposito Hum Mol Genet 22:3654, 2013 XL APOL1 Apolipoprotein L-1 Parsa NEJM 369:2183, 2013 Unknown AR, autosomal recessive; AD, autosomal dominant; XL; X-linked; Unknown, mode of inheritence not clearly characterized. Supplementary Table 1c. 17 genes that represent monogenic causes of human nephritis, if mutated (Note that underlined gene indicates that we identified a variant in this gene as the causative mutation in this cohort) Mode of Gene Protein Reference Inheritenance ADAM metallopeptidase with thrombospondin ADAMTS13 Levy Nature 413: 488, 2001 AR type 1 motif 13 CFI Complement factor I Fremeaux-Bacchi J Med Genet 41:e84, 2004 AR COL4A4 Collagen type IV alpha 4 chain Mochizuki Nat Genet 8:77, 1994 AR CFB CFB Goicoechea de Jorge Proc Nat Acad Sci 104:240, 2007 AD CFHR3 CFHR3 Zipfel PLoS Genet 3:e41, 2007 AD CFHR5 Complement factor H related 5 Gale Lancet 376:794, 2010 AD FN1 Fibronectin Castelletti Proc Nat Acad Sci 105:2538, 2008 AD FOXC2 Forkhead Box C2 Yildirim-Toruner AJMG 131A:281, 2004 AD THBD Thrombomodulin Delvaeye NEJM 361:345, 2009 AD SPRY2 Sprouty RTK Signaling Antagonist 2 Milillo Europ J Hum Genet 23:1673, 2015 AD C3 Complement C3 Fremeaux-Bacchi Blood 112:4948, 2008 AR/AD CD46 CD46 molecule Noris Lancet 362:1542, 2003 AR/AD CFH Complement factor H Edelsten Arch Dis Child 53:255, 1978 AR/AD CFHR1 Complement factor H related 1 Zipfel PLoS Genet 3:e41, 2007 AR/AD COL4A3 Collagen type IV alpha 3 chain Lemmink Hum Mol Genet 3:1269, 1994 AR/AD COL4A5 Collagen type IV alpha 5 chain Antignac J Clin Invest 93:1195, 1994 XL COL4A6 Collagen type IV alpha 6 chain Renieri Hum Mutat 4:195, 1994 XL AR, autosomal recessive; AD, autosomal dominant; XL; X-linked. Supplementary Table 1d: 95 genes that represent monogenic causes of human nephronophthisis or cystic disease, if mutated (Note that underlined gene indicates that we identified a variant in this gene as the causative mutation in this cohort) Mode of Gene Alias Protein Reference Inheritenance AHI1 JBTS3 Abelson Helper Integration Site 1 Parisi J Med Gen 43:334 ,2005 AR ALMS1 ALMS Altrom Syndrome Collin Nat Genet. 31:74, 2002 AR Ankyrin repeat and sterile alpha motif ANKS6 NPHP16 Hoff Nat Genet 45:951, 2013 AR domain containing 6 ARL6 BBS3 Meckel syndrome, type 1 Khaddour Hum Mutat 28, 523, 2007 AR ARL13B JBTS8 ADP-ribosylation factot-like 13B Cantagrel AJHG 83:170, 2008 AR B9D1 MKS9 B9 domain containing protein 1 Romani Orphanet J Rare Dis 9:72, 2014 AR B9D2 MKS10 B9 domain containing protein 2 Dowdle AJHG 89: 94, 2011 AR BBIP1 BBS18 Bardet-Biedl Syndrome 18 Scheidecker J Med Genet 51:132, 2014 AR BBS1 BBS1 Bardet-Biedl Syndrome 1 Mykytyn Nat Genet 31:435, 2002 AR BBS2 BBS2 Bardet-Biedl Syndrome 2 Katsanis Science 293:2256, 2001 AR BBS4 BBS4 Bardet-Biedl Syndrome 4 Mykytyn Nat Genet 8:188, 2001 AR BBS5 BBS5 Bardet-Biedl Syndrome 5 Tieder Int J Pediatr Nephrol 3:199, 1982 AR BBS7 BBS7 Bardet-Biedl Syndrome 7 Badano AJHG 72:650, 2003 AR BBS10 BBS10 Bardet-Biedl Syndrome 10 Stoetzel Nat Genet 38:521, 2006 AR BBS12 BBS12 Bardet-Biedl Syndrome 12 Stoetzel AJHG 80:1, 2007 AR C2CD3 OFD14 Orofaciodigital syndrome 14 Thauvin-Robinet Nature Genet 46:905, 2014 AR C5orf42 JBTS17 5 open reading frame 42 Srour AJHG 90:693, 2012 AR Coiled-coil and C2 domains-containing CC2D2A JBTS9 Noor AJHG 82:1011, 2008 AR protein 2A CCDC41 CEP83 Coiled-coil domain containing 41 Failler AJHG 94:905, 2014 AR CEP41 TSGA14 Centrosomal protein 41kDa Lee Nat Genet 44:193, 2012 AR Korvatska Am J Med Genet B Neuropsychiatr CEP104 JBTS25 Centrosomal protein 41kDa AR Genet 156B:303, 2011 CEP120 SRTD13 Centrosomal protein 120kDa Shaheen Hum Mol Genet. 24:1410, 2015 AR CEP164 NPHP15 Centrosomal protein 164kDa Chaki Cell 150:533, 2012 AR CEP290 NPHP6 Centrosomal protein 290kDa Sayer Nat Genet 38:674, 2006 AR Centrosome spindle pole-associated CSPP1 JBTS21 Akizu AJHG 94:80, 2014 AR protein 1 Double-cortin domain containing DCDC2 NPHP19 Schueler AJHG 96:81, 2015 AR protein 2 DDX59 OFD5 Orofaciodigital syndrome 5 Shamseldin AJHG 93:555, 2013 AR DYNC2H1 SRTD3 Dynein cystoplasmic 2 heavy chain El Hokayem J Med Genet 49:227, 2012 AR FAN1 MTMR15 FANCI-associated nuclease 1 Zhou Nat Genet 44:910, 2012 AR GLIS2 NPHP7 GLIS Family Zinc Finger 2 Attanasio Nat Genet 39:1018, 2007 AR 17-Beta-Hydroxysteroids hydrogenase HSD17B4 MFP2 Boehmer J Clin Endocrinol Metab 84:4713, 1999 AR IV IFT27 BBS20 Bardet-Biedl Syndrome 20 Schaefer J Med Genet 61:447 2016 AR IFT43 CED3 Intraflagellar transport 43 Gilissen AJHG 87:418, 2010 AR IFT52 SRTD Intraflagellar Transport 52 Girisha Clin Genet. 90:536, 2016 AR IFT57 Intraflagellar Transport 57 Bruel J Med Genet 54:371, 2017 AR IFT80 SRTD2 Intraflagellar Transport 80 Beales Nat Genet 39:727 2007 AR IFT81 CDV-1 Intraflagellar Transport 81 Perrault J Med Genet 52:657, 2015 AR IFT122 CED1 Intraflagellar transport 122 Walczak-Sztulpa AJHG 86:949, 2010 AR IFT140 SRTD9 intraflagellar transport 140 Perrault AJHG 90:864, 2012 AR Intraflagellar transport 172 homolog IFT172 NPHP17 Halbritter AJHG 93:915, 2013 AR (Chlamydomonas) INPP5E JBTS1 Inositol polyphosphate-5-phosphatase Bielas Nat Genet 41:1032, 2009 AR INVS NPHP2 Inversin Otto Nat Genet 34:413, 2003 AR IQCB1 NPHP5 IQ motif containing B1 Otto Nat Genet 37:282, 2005 AR KIAA0556 JBTS26 Katanin-intereacting protein Saunders Genome Biol 16:293, 2015 AR KIAA0586 JBTS23 TALPID 3, chicken homolog of Bachmann-Gagescu Hum Mutat 36:831, 2015 AR KIAA0753 OFD15 Orofaciodigital syndrome 15 Chevrier Hum Mol Genet 25:497, 2016 AR KIF7 JBTS12 Kinesin family member 7 Putoux Nat Genet 43:601, 2011 AR KIF14 MKS12 Kinesin family member 14 Filges Clin Genet 86:220, 2013 AR LZTFL1 BBS17 Bardet-Biedl syndrome 17 Marion J Med Genet 49:317, 2012 AR Mitogen activated protein kinase- MAPKBP1 NPHP20 Macia AJHG 100:323, 2017 AR binding protein 1 MKKS BBS6 Bardet-Biedl Syndrome 6 Katsanis Nat Genet 26:67, 2000 AR MKS1 MKS1 Meckel syndrome, type 1 Kyttälä Nat Genet 38:155, 2006 AR NEK1 SRTD6 NIMA Related Kinase 1 Thiel AJHG 88:106, 2011 AR NIMA (never in mitosis gene a) - NEK8 NPHP9 Otto JASN 19:587, 2008 AR related kinase 8 NPHP1 NPHP1 Nephrocystin 1 Hildebrandt Nat Genet 17:149, 1997 AR NPHP3 Nephrocystin 3 Olbrich Nat Genet 34:455, 2003 AR NPHP4 Nephronophthisis 4 Otto AJHG 71:1161, 2002 AR PDE6D JBTS22 Phosphodiesterase 6D Thomas Hum Mutat 35:137, 2014 AR Phosphatidyllinositol 3-kinase, PIK3R4 VPS15 Panaretou J Biol Chem 272: 2477, 1997 AR regulatorry subunit 4 PKHD1 ARPKD PKHD1, Fibrocystin/Polyductin Bergmann Kidney Int 67:829 2005 AR PTHB1 BBS9 Bardet-Biedl Syndrome 9 Nishimura AJHG 77:1021, 2005 AR RPGRIP1L NPHP8 RPGRIP1 Like Arts Nat Genet 39:882, 2007 AR Serologically Defined Colon Cancer SDCCAG8 NPHP10 Otto Nat Genet 42:840, 2010 AR Antigen 8 SCLT1 OFD9 Orofaciodigital syndrome 9 Adly Hum Mutation 35:36, 2013 AR Solute carrier member family 41, SLC41A1 Hurd JASN 24:967, 2013 AR member 1 TCTN1 JBTS13 Tectonic family member 1 Garcia-Gonzalo Nat Genet 43:776, 2011 AR TCTN2 JBTS24 Tectonic family member 2 Huppke Eur J Hum Genet 23:616, 2015 AR TCTN3 JBTS18 Tectonic family member 3 Thomas AJHG 91:372, 2012 AR TMEM67 NPHP11 Transmembrane Protein 67 Otto J Med Genet 46:663, 2009 AR TMEM107 MKS13 Transmembrane Protein 107 Shasheen Hum Mol Genet 24:5211, 2015 AR TMEM138 JBTS16 Transmembrane Protein 138 Lee Science 335:966, 2012 AR TMEM216 JBTS2 Transmembrane Protein 216 Edvardson AJHG 86:93, 2010 AR TMEM231 JBTS20 Transmembrane Protein 231 Srour J Med Genet 49:636, 2012 AR TMEM237 JBTS14 Transmembrane Protein 237 Huang AJHG 89:713, 2011 AR TNF receptor-associated factor 3- TRAF3IP1 SLS9 Berbari Dev Biol 360:66, 2011 AR interacting protein 1 TRIM32 BBS11 Bardet-Biedl Syndrome 11 Chiang Proc Natl Acad Sci USA 103:6287,2006 AR TTC8 BBS8 Bardet-Biedl Syndrome 8 Stoetzel J Hum Genet 51:81, 2005 AR TTC21B NPHP12 Tetratricopeptide Repeat Domain 21B Davis Nat Genet 43:189, 2011 AR Thioredoxin domain-containing protein TXNDC15 Honjo Cell Rep 16:295, 2016 AR 15 WD repeat-containing planar cell WDPCP BBS15 Stone Nat Genet 25:79, 2000 AR polarity effector WDR19 NPHP13 WD repeat domain 19 Bedrup AJHG 89:634, 2011 AR WDR34 SRTD11 WD repeat domain 34 Schmidts AJHG 93:932, 2013 AR WDR35 CED2 WD repeat domain 35 Gilissen AJHG 87:418, 2010 AR WDR60 SRTD8 WD repeat domain 60 McInerney-Leo AJHG 93: 515, 2013 AR XPNPEP3 NPHPL1 X-prolyl aminopeptidase 3 O'Toole J Clin Invest 120:791, 2010 AR ZNF423 NPHP14 Zinc finger protein 423 Chaki Cell 150:533, 2012 AR Coiled-coil domain containing protein CCDC28B Cardenas-Rodriguez Hum Genet 132:91, 2013 AR/DR 28B EVC EvC Ciliary Complex Subunit 1 Ruiz-Perez Nat Genet. 24:283, 2000 AR/AD EVC2 EvC Ciliary Complex Subunit 2 Kurian Indian J Dent Res. 18:31, 2007 AR/AD HOXA4 Homobox A4 Acampora Nucleic Acids Res 17:10385, 1985 AD HOXB6 Homobox B6 Kaur J Exp Zool 264:323, 1992 AD Polycystin 1, Transient Receptor PKD1 Rossetti JASN 18:2143, 2007 AD Potential Channel Interacting Polycystin 2, Transient Receptor PKD2 Rossetti JASN 18:2143, 2007 AD Potential Cation Channel UMOD Uromodulin Hart J Med Genet 39:882, 2002 AD OFD1 Orofaciodigital syndrome I Feather Hum Mol Genet 6:1163, 1997 XLD AR, autosomal recessive; AD, autosomal dominant; DR, digenic recessive; XLD; x-linked dominant. Supplementary Table 1e. 37 genes that represent monogenic causes of human nephrolithiasis or nephrocalcinosis, if mutated (Note that underlined gene indicates that we identified a variant in this gene as the causative mutation in this cohort) Mode of Gene Protein Reference Inheritenance AGXT Alanine-glyoxylate aminotransferase Purdue Proc Natl Acad Sci U S A 88:10900, 1991 AR ALDOB Aldolase B fructose biphosphate Paolella Hum Genet 77:115, 1987 AR ALPL Alkaline Phosphatase, Weiss Proc Natl Acad Sci U S A 85:7666, 1988 AR APRT Adenine phosphoribosyltransferase Hidaka J Clin Invest 80:1409, 1987 AR ATP6V0A4 ATPase, H+ transporting, lysosomal V0 subunit a4 Smith Nat Genet 26:71, 2000 AR ATP6V1B1 ATPase, H+ transporting, lysosomal 56/58kDa, V1 subunit B1 Karet Nat Genet 21:84, 1999 AR ATP7B ATPase, Cu(2+)-transporting, beta polypeptide Gromadzka Clin Genet 68:524, 2005 AR CA2 Carbonic anhydrase II Venta AJMG 49:1082, 1991 AR CLCNKB Chloride channel, voltage-sensitive Kb Simon Nat Genet 17:171, 1997 AR CLDN16 Claudin 16 Simon Science 285:103, 1999 AR CLDN19 Claudin 19 Konrad AJHG 79:949, 2006 AR CTNS Cystinosin Town Nat Genet 18:319, 1998 AR CYP24A1 Cytochrome P450, family 24, subfamily A, polypeptide 1 Schlingmann NEJM 36:410, 2011 AR FAH Fumarylacetoacetate hydrolase Aponte Proc Nat Acad Sci 98:641, 2001 AR FAM20A Family with sequence similarity 20, member A Jaureguiberry Nephron Physiol 122:1, 2012 AR G6PC Glucose 6 phosphate catalytic Seydewitz Hum Mutat 15:115, 2000 AR GRHPR Glyoxylate reductase/hydroxypyruvate Cramer Hum Mol Genet 8:2063, 1999 AR HOGA1 4-hydroxy-2-oxoglutarate aldolase 1 Belostotsky AJHG 87:392, 2010 AR KCNJ1 Potassium inwardly-rectifying channel, subfamily J, member 1 Simon Nat Genet 14:152, 1996 AR SLC12A1 Solute carrier family 12, member 1 Simon Nat Genet 13:183, 1996 AR SLC26A1 Solute carrier family 26 (sulfate transporter), member 1 Gee AJHG 98:1228, 2016 AR SLC2A2 Solute carrier family 2 (faciliated glucose transporter) Akagi J Hum Genet 45:60, 2000 AR SLC34A3 Solute carrier family 34 (sodium Lorenz-Depiereux AJHG 78:193, 2006 AR XDH Xanthine dehydrogenase Ichida J Clin Invest 99:2391, 1997 AR HNF4A Hepatocyte nuclear factor 4, alpha Hamilton J Med Genet 51:165, 2014 AD Solute carrier family 9, subfamily A SLC9A3R1 Karim NEJM 359:1128, 2008 AD (NHE3, cation proton antiporter 3), member 3 regulator 1 CASR Calcium-sensing receptor Pearce NEJM 335:1115, 1996 AD/AR SLC22A12 Solute carrier family 22 (organic Enomoto Nature 417:447, 2002 AD/AR SLC2A9 Solute carrier family 2 (facilitated Matsuo AJHG 83:744, 2008 AD/AR SLC34A1 Solute carrier family 34 (sodium Prie NEJM 347:983, 2002 AD/AR Solute carrier family 3, member 1 SLC3A1 (cystine, dibasic and neutral transporters, activator of Calonge Nat Genet 6:420, 1994 AD/AR cystine, dibasic and neutral amino acid transport Solute carrier family 4, anion exchanger, member 1 SLC4A1 Bruce J Clin Invest 100:1693, 1997 AD/AR (erythrocyte membrane) SLC7A9 Solute carrier family 7 (glycoprotein associated Feliubadalo Nat Genet 23:52, 1999 AD/AR VDR Vitamin D (1,25- dihydroxyvitamin D3) receptor Scott JASN 10:1007, 1999 AD/AR CLCN5 Chloride channel, voltage-sensitive 5 Lloyd Nature 379:445, 1996 XL HPRT1 Hypoxanthine Davidson AJHG 48:951, 1991 XL OCRL Oculocerebrorenal syndrome of Lowe Reilly AJHG 42:748, 1988 XL AR, autosomal recessive; AD, autosomal dominant; DR, digenic recessive; XLD; X-linked recessive. Supplementary Table 1f. 145 genes that represent monogenic causes of human syndromic CAKUT, if mutated (Note that underlined gene indicates that we identified a variant in this gene as the causative mutation in this cohort) Mode of Gene Protein Reference Inheritenance B3GALTL Beta 3-Glucosyltransferase Lesnik Oberstein Am J Hum Genet 79:562, 2006 AR BSCL2 BSCL2, Seipin Lipid Droplet Biogenesis Associated Haghighi Clin. Genet. 89: 434, 2016 AR CD151 CD151 Molecule (Raph Blood Group) Karamatic Blood 104:2217, 2004 AR CD96 CD96 Molecule Kaname AJHG 81:835, 2007 AR CHRNG Cholinergic Receptor Nicotinic Gamma Subunit Vogt J Med Genet 49:21, 2012 AR CISD2 CDGSH Iron Sulfur Domain 2 Amr AJHG 81:673, 2007 AR CTU2 Cytosolic Thiouridylase, subunit 2 Shaheen AJMG 170:3222, 2016 AR CYP21 Cytochrome P450 Family 21 Martul Arch Dis Child 55:324, 1980 AR DACH1 Dachshund Family Transcription Factor 1 Schild Nephrol Dial Transplant 28:227, 2013 AR DHCR7 7-Dehydrocholesterol Reductase Löffler AJHG 13;95:174, 2000 AR EMG1 EMG1, N1-Specific Pseudouridine Methyltransferase Armistead AJHG 84:728, 2009 AR Establishment Of Sister Chromatid Cohesion N- ESCO2 Vega J Med Genet 47:30, 2010 AR Acetyltransferase 2 ETFA Electron Transfer Flavoprotein Alpha Subunit Lehnert Eur J Pediatr 139:56, 1982 AR ETFB Electron Transfer Flavoprotein Beta Subunit Lehnert Eur J Pediatr 139:56, 1982 AR ETFDH Electron Transfer Flavoprotein Dehydrogenase Lehnert Eur J Pediatr 139:56, 1982 AR FANCA Fanconi Anemia Complementation Group A Joenje & Patel Nat Rev Genet 2:466, 2001 AR FANCB Fanconi Anemia Complementation Group B McCauley Am J Med Genet A 155A:2370, 2011 AR FANCD2 Fanconi Anemia Complementation Group D2 Kalb AJHG 80:895, 2007 AR FANCE Fanconi Anemia Complementation Group EWegner Clin Genet 50:479, 1996 AR FANCI Fanconi Anemia Complementation Group I Savage AJMG 170A:386, 2015 AR FANCL Fanconi Anemia Complementation Group L Vetro Hum Mutat 36:562, 2015 AR FAT4 FAT Atypical Cadherin 4 Alders Hum Genet 133:1161, 2014 AR FOXP1 Forkhead Box P1 Bekheirnia Genet Med 19:412, 2017 AR HES7 Hes Family BHLH Transcription Factor 7 Sparrow Hum Mol Genet 17:3761, 2008 AR HYLS1 HYLS1, Centriolar And Ciliogenesis Associated Paetau J Neuropathol Exp Neurol 67:750, 2008 AR IFT46 Intraflagellar Transport 46 Lee Dev Biol 400:248, 2015 AR IFT74 Intraflagellar Transport 74 Cevik PLoS GeneT 9:e1003977, 2013 AR INPP5E Inositol Polyphosphate-5-Phosphatase E Travaglini Eur J Hum Genet 21:1074, 2013 AR ITGA3 Integrin Subunit Alpha 3 Yalcin Hum Mol Genet 24:3679, 2015 AR JAM3 Junctional Adhesion Molecule 3 Mochida Am J Hum Genet 10;87:882, 2010 AR LFNG O-Fucosylpeptide 3-Beta-N- LFNG Sparrow Am J Hum Genet 78:28, 2006 AR Acetylglucosaminyltransferase LMNA Lamin A/C Klupa Endocrine 36:518, 2009 AR LRP2 LDL Receptor Related Protein 2 Kantarci Nat Genet 39:957, 2007 AR LRP4 LDL Receptor Related Protein 4 Li Am J Hum Genet 86:696, 2010 AR MESP2 Mesoderm Posterior BHLH Transcription Factor 2 George-Abraham Am J Med Genet A 158A:1971, 2012 AR MKS3 Meckel Syndrome Type 3 Protein Baala Am J Hum Genet 80:186, 2007 AR PEX5 Peroxisomal Biogenesis Factor 5 Sundaram Nat Clin Pract Gastroenterol Hepatol 5:456, 2008 AR PMM2 Phosphomannomutase 2 Horslen Arch Dis Child 66:1027, 1991 AR PROK2 Prokineticin 2 Madan Mol Genet Metab Rep 12:57, 2017 AR RECQL4 RecQ Like Helicase 4 Siitonen Eur J Hum Genet 17:151, 2009 AR ROR2 Receptor Tyrosine Kinase Like Orphan Receptor 2 Wiens Clin Genet 37:481, 1990 AR RPS19 Ribosomal Protein S19 Hoefele Pediatr Nephrol 25:1255, 2010 AR SCARF2 Scavenger Receptor Class F Member 2 Anastasio Am J Hum Genet 87:553, 2010 AR STRA6 Stimulated By Retinoic Acid 6 Golzio Am J Hum Genet 80:1179, 2007 AR TMCO1 Transmembrane And Coiled-Coil Domains 1 Xin Proc Natl Acad Sci U S A 107:258, 2010 AR TWIST2 Twist Family BHLH Transcription Factor 2 Stevens Am J Med Genet 107:30, 2002 AR UBR1 Ubiquitin Protein Ligase E3 Component N-Recognin 1 Vanlieferinghen Genet Couns 14:105, 2003 AR PEX1 Peroxisomal Biogenesis Factor 1 Crane Hum Mutat 26:167, 2005 AR PIGL Phosphatidylinositol Glycan Anchor Biosynthesis Class L Schnur Am J Med Genet 72:24, 1997 AR PIGO Phosphatidylinositol Glycan Anchor Biosynthesis Class O Krawitz Am J Hum Genet 91:146, 2012 AR PIGN Phosphatidylinositol Glycan Anchor Biosynthesis Class N Ohba Neurogenetics 15:85, 2014 AR PIGT Phosphatidylinositol Glycan Anchor Biosynthesis Class T Nakashima Neurogenetics 15:193, 2014 AR PIGV Phosphatidylinositol Glycan Anchor Biosynthesis Class V Horn Eur J Hum Genet 22:762, 2014 AR PIGY Phosphatidylinositol Glycan Anchor Biosynthesis Class Y Ilkovski Hum Mol Genet 24:6146, 2015 AR PTF1A Specific Transcription Factor, 1a Gurung Mol Med Rep 12:1579, 2015 AR WFS1 Wolframin ER Transmembrane Glycoprotein Salih Acta Paediatr Scand 80:567, 1991 AR WNT3 Wnt Family Member 3 Niemann Am J Hum Genet 74:558, 2004 AR ZMPSTE24 Zinc Metallopeptidase STE24 Chen Am J Med Genet A 149A:1550, 2009 AR ACTB Actin Beta Rivière Nat Genet 44:440, 2012 AD ACTG1 Actin Gamma 1 Rivière Nat Genet 44:440, 2012 AD AIFM3 Apoptosis Inducing Factor, Mitochondria Associated 3 Lopez-Rivera NEJM 376:742, 2017 AD BICC1 BicC Family RNA Binding Protein 1 Kraus Hum Mutat 33:86, 2012 AD BMP7 Bone Morphogenetic Protein 7 Hwang Kidney Int 85:1429, 2014 AD BRAF B-Raf Proto-Oncogene, Serine/Threonine Kinase Sarkozy Hum Mutat 30:695, 2009 AD CDC5L Cell Division Cycle 5 Like Groenen Genomics 49:218, 1998 AD CREBBP CREB Binding Protein Kanjilal J Med Genet 29:669, 1992 AD EP300 E1A Binding Protein P300 Roelfsema Am J Hum Genet 76:572, 2005 AD ESRRG Estrogen Related Receptor Gamma Harewood PLoS One 5:e12375, 2010 AD FBN1 Fibrillin 1 Tokhmafshan Pediatr Nephrol 32:565, 2017 AD FGFR1 Fibroblast growth factor receptor 1 Farrow AJHG 140A:537, 2006 AD FGFR3 Fibroblast growth factor receptor 3 Rohmann Nat Genet 38:495, 2006 AD Milunsky Clin Genet 69:349, 2006; Bamforth Am J Med Genet FGF10 Fibroblast Growth Factor 10 AD 43:932, 1992 FGF8 Fibroblast Growth Factor 8 Falardeau J Clin Invest 118:2822 2008 AD FMN1 Formin 1 Dimitrov J Med Genet 47:569, 2010 AD FOXC1 Forkhead Box C1 LeHeup Eur J Pediatr 154:130, 1995 AD FOXF1 Forkhead Box F1 Hilger Hum Mutat 36:1150, 2015 AD GDF3 Growth Differentiation Factor 3 Karaca Am J Med Genet A 167A:2795, 2015 AD GFRA1 GDNF Family Receptor Alpha 1 Chatterjee Hum Genet 131:1725, 2013 AD GLI2 GLI Family Zinc Finger 2 Carmichael J Urol 190:1884, 2013 AD HOXA13 Homeobox A13 Halal Am J Med Genet 30:793, 1998 AD HOXD13 Homeobox D13 Garcia-Barceló Am J Med Genet A 146A:3181, 2008 AD JAG1 Jagged 1 Kamath Nat Rev Nephrol 9:409, 2013 AD KAT6B Lysine Acetyltransferase 6B Campeau Am J Med Genet 90:282, 2012 AD KCTD1 Potassium Channel Tetramerization Domain Containing 1 Marneros Am J Hum Genet 92:621, 2013 AD

KCNH2 Potassium Voltage-Gated Channel Subfamily H Member 2 Caselli Am J Med Genet 146A:1195, 2008 AD KRAS KRAS Proto-Oncogene, GTPase Schubbert Nat Gene 38:331, 2006 AD LIM Domain Containing Preferred Translocation Partner In LPP Hernández-García Am J Med Genet A 158A:1785, 2012 AD Lipoma MLL2/ KMT2D Myeloid/Lymphoid Or Mixed-Lineage Leukemia Protein 2 Banka Eur J Hum Genet 20:381, 2012 AD MYCN Feingold Syndrome Marcelis Hum. Mut. 29:1125, 2006 AD NFIX Nuclear Factor I X Malan Am J Hum Genet 87:189, 2010 AD NOTCH2 Notch 2 Kamath Nat Rev Nephrol 9:409, 2013 AD PAX8 Paired Box 8 Meeus J Clin Endocrinol Metab 89:4285, 2004 AD PROKR2 Prokineticin Receptor 2 Sarfati Front Horm Res 39:121, 2010 AD PTPN11 Protein Tyrosine Phosphatase, Non-Receptor Type 11 Bertola Am J Med Genet 130A:378, 2004 AD RAF1 Raf-1 Proto-Oncogene, Serine/Threonine Kinase Razzaque Nat Genet 39:1013, 2007 AD RAI1 Retinoic Acid Induced 1 Vilboux PLoS One 6:e22861, 2011 AD SALL4 Spalt Like Transcription Factor 4 Kohlhase GeneReviews®Book Section, 1993 AD SEMA3A Semaphorin 3A Young Hum Reprod 27:1460, 2012 AD SEMA3E Semaphorin 3E Lalani J Med Genet 41:e94, 2004 AD SETBP1 SET Binding Protein 1 Schinzel Am J Med Genet 1:361, 1978 AD SHH Sonic Hedgehog Lurie Am J Med Genet 35:286, 1990 AD SF3B4 Splicing Factor 3b Subunit 4 Bernier Am J Hum Genet 90:925, 2012 AD SNAP29 Synaptosome Associated Protein 29 Lopez-Rivera NEJM 376:742, 2017 AD SOS1 SOS Ras/Rac Guanine Nucleotide Exchange Factor 1 Ferrero Eur J Med Genet 51:566, 2008 AD SOX9 SRY-Box 9 Airik Hum Mol Genet 19:4918, 2010 AD SRCAP Snf2 Related CREBBP Activator Protein Hood Am J Hum Genet 90:308, 2012 AD TBX1 T-Box 1 Kujat Am J Med Genet A 140:1601, 2006 AD TBX3 T-Box 3 Meneghini Eur J Med Genet 49:151, 2006 AD TFAP2A Transcription Factor AP-2 Alpha Milunsky Am J Hum Genet 82:1171, 2008 AD TP63 Tumor Protein P63 Celli Cell 99:143, 1999 AD TSC1 Tuberous Sclerosis 1 Curatolo Lancet 372:657, 2008 AD TSC2 Tuberous Sclerosis 2 Kumar Hum Mol Genet 4:1471, 1995 AD WNT5A Wnt Family Member 5A Roifman Clin Genet 87:34, 2015; Person Dev Dyn 239:327, 2010 AD ARID1B AT-Rich Interaction Domain 1B Levy J Med Genet 28, 1991 AD/ AR DIS3L2 DIS3 Like 3'-5' Exoribonuclease 2 Astuti Nat Genet 5;44:277, 2012 AD/ AR FGFR2 Fibroblast Growth Factor Receptor 2 LeHeup Eur J Pediatr 154:130, 1995 AD/ AR GDF6 Growth Differentiation Factor 6 Tassabehji Hum Mutat 29:1017, 2008 AD/ AR GLI3 GLI Family Zinc Finger 3 Cain PLoS One 4:e7313, 2009 AD/ AR PCSK5 Proprotein Convertase Subtilisin & Kexin Type 5 Nakamura BMC Res Notes 8:228, 2015 AD/ AR PTEN Phosphatase And Tensin Homolog Reardon J Med Genet 38:820, 2001 AD/ AR RPS24 Ribosomal Protein S24 Yetgin Turk J Pediatr 36:239, 1994 AD/ AR VANGL1 VANGL Planar Cell Polarity Protein 1 Bartsch Mol Syndromol 3:76, 2012 AD/ AR AXIN1 Axin 1 Oates Am J Hum Genet 79:155, 2006 Sporadic H19, Imprinted Maternally Expressed Transcript (Non-Protein H19 Hur Proc Natl Acad Sci U S A 113:10938, 2016 Sporadic Coding) KCNQ1 Opposite Strand & Antisense Transcript 1 (Non- KCNQ1OT1 Chiesa Hum Mol Genet 21:10, 2012 Sporadic Protein Coding) NIPBL NIPBL, Cohesin Loading Factor Rohatgi Am J Med Genet 152A:1641, 2010 Sporadic CDKN1C Cyclin Dependent Kinase Inhibitor 1C Mussa Pediatr Nephrol 27:397, 2012 Sporadic CHD7 Chromodomain Helicase DNA Binding Protein 7 Janssen Hum Mutat 33:1149 2012 Sporadic AMER1 APC Membrane Recruitment Protein 1 Pellegrino Am J Med Genet 16:159, 1997 XL ATP7A ATPase Copper Transporting Alpha Vulpe Nat Genet 3:7, 1993 XL BCOR BCL6 Corepressor Ng Nat Genet 36:411, 2004 XL FAM58A Family With Sequence Similarity 58 Member A Green J Med Genet 33:594, 1996; Unger Nat Genet 40:287, 2008 XL FLNA Filamin A Robertson Am J Med Genet A 140:1726, 2006 XL GPC3 Glypican 3 Cottereau Am J Med Genet C Semin Med Genet 163:92, 2013 XL MID1 Midline 1 Preiksaitiene Clin Dysmorphol 24:7, 2015 XL NSDHL NAD(P) Dependent Steroid Dehydrogenase-Like König J Am Acad Dermatol 46:594, 2002 XL PIGA Phosphatidylinositol Glycan Anchor Biosynthesis Class A Johnston Am J Hum Genet 90:295, 2012 XL PORCN Porcupine O-Acyltransferase Suskan Pediatr Dermatol 7:283, 1990 XL SMC1A Structural Maintenance Of 1A Deardorff GeneReviews® Book Section Seattle(WA), 1993 XL UPF3B UPF3B, Regulator Of Nonsense Mediated MRNA Decay Lynch Eur J Med Genet 55:476, 2012 XL ZIC3 Zic Family Member 3 Chung Am J Med Genet 155:1123, 2011 XL GDF11 Growth Differentiation Factor 11 Tsuda Eur J Pediatr Surg 21:238, 2011 Unknown OSR1 Odd-Skipped Related Transciption Factor 1 Zhang Hum Mol Genet 20:4167, 2011 Unknown TTC30A Tetratricopeptide Repeat Domain 30A Hilger Hum Mutat 36:1150, 2015 Unknown SH2B1 SH2B Adaptor Protein 1 Sampson Am J Med Genet 152:2618, 2010 Unknown AR, autosomal recessive; AD, autosomal dominant; XL; X-linked; Unknown, mode of inheritence not clearly characterized. Supplementary Table 1g: 11 genes that represent rare monogenic causes of human kidney disease (miscellaneous category), if mutated Mode of Gene Protein Reference Inheritenance CPT2 Carnitine Palmitoyltransferase 2 Vivante Pediatr Nephrol 32:2273, 2017 AR EIF2AK3 Eukaryotic Translation Initiation Factor 2 Alpha Kinase 3 Delepine Nature Genet 25:406, 2000 AR DLL4 Delta-like 4 Meester AJHG 97:475, 2015 AD GSN Gelsolin Maury FEBS Lett 260:85, 1990 AD LYZ Lysozyme Pepys Nature 362:553, 1993 AD SDHB Succinate Dehydrogenase Complex Iron Sulfur Subunit B Astuti AJHG 69:49, 2001 AD Badenhop Genes Chromosomes Cancer 31:255, SDHD Succinate Dehydrogenase Complex Subunit D AD 2001 TMEM127 Transmembrane Protein 127 Qin Nature Genet. 42:229, 2010 AD Inhibitor of kappa light polypeptide gene enhancer in B IKBKAP Anderson AJHG 68:753, 2001 AD/AR cells, kinase complex associated protein VHL Von Hippel-Lindau Tumor Suppressor Latif Science 260:1317, 1993 AD/AR GLA Galactosidase alpha Bernstein J Clin Invest 83:1390, 1989 XL AR, autosomal recessive; AD, autosomal dominant; XL; X-linked. Supplementary Table 2. Information on 6 out of 396 known chronic kidney disease genes which did not achieve a mean coverage of at least 30X.

Mean X Mean 10x Gene Protein Disease category coverage coverage BBIP1 Bardet-Biedl Syndrome 18 Cystic Kidney Disease 24 66.7% CYP24A1 Cytochrome P450 Family 24 Nephrolithiasis/ 29.8 92.8% Subfamily A Member 1 Nephrocalcinosis GREB1L GREB1 Like Retinoic Acid Isolated CAKUT 14.1 23.9% Receptor Coactivator PIGY Phosphatidylinositol Glycan Syndromic 28.6 91.7% Anchor Biosynthesis Class Y CAKUT PROK2 Prokineticin 2 Syndromic 27 91.3% CAKUT PTEN Phosphatase And Tensin Syndromic 22 65.5% Homolog CAKUT

Mean X coverage, average number of reads that align to the targeted exon; Mean 10X coverage, percentage of bases within each gene that achieve a coverage ≥10X.

Supplementary Table 3. ACMGa guidelines for variant calling.

Family Gene Variant Classifi- Criterion (ESPb, 1000 cation genomesc, ExACd) B910 4p16.3 Heterozygous N/A N/A deletion Deletion B643 17q12 Heterozygous N/A N/A deletion Deletion B949 AGXT NM_000030.2: Pathogenic PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.25_26insC splice sites, initiation codon, single or multiexon p.K12Qfs*156 deletion) in a gene where LOF is a known mechanism of (NP, NP, disease 0.00046) PS1 Same amino acid change as a previously established pathogenic variant regardless of nucleotide change PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology

NM_000030.2: Pathogenic PS1 Same amino acid change as a previously established c.508G>A pathogenic variant regardless of nucleotide change p.G170R PS3 Well-established in vitro or in vivo functional studies (0.0015, NP, supportive of a damaging effect on the gene or gene 0.001) product PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B2404 AGXT NM_000030.2: Pathogenic PS1 Same amino acid change as a previously established c.245G>A pathogenic variant regardless of nucleotide change p.G82E PS3 Well-established in vitro or in vivo functional studies (NP, NP, supportive of a damaging effect on the gene or gene 1.7e-5) product PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B942 AGXT NM_000030.2: Pathogenic PS1 Same amino acid change as a previously established c.473C>T pathogenic variant regardless of nucleotide change p.S158L PS3 Well-established in vitro or in vivo functional studies (NP, NP, NP) supportive of a damaging effect on the gene or gene product PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B2440 COL4A5 NM_000495.4: Pathogenic PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.4791T>G splice sites, initiation codon, single or multiexon p.Y1597* deletion) in a gene where LOF is a known mechanism of (NP, NP, NP) disease PS1 Same amino acid change as a previously established pathogenic variant regardless of nucleotide change PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology A4037 CEP83 NM_016122.2: Pathogenic PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.2007delA splice sites, initiation codon, single or multiexon p.E669Dfs*14 deletion) in a gene where LOF is a known mechanism of (NP, NP, NP) disease PS1 Same amino acid change as a previously established pathogenic variant regardless of nucleotide change PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B659 CEP83 NM_016122.2: Pathogenic PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.2007delA splice sites, initiation codon, single or multiexon p.E669Dfs*14 deletion) in a gene where LOF is a known mechanism of (NP, NP, NP) disease PS1 Same amino acid change as a previously established pathogenic variant regardless of nucleotide change PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B06 DYNC2H1 NM_001377.2: Likely PM1 Located in a mutational hot spot and/or critical and well- c.9638A>G Pathogenic established functional domain (e.g., active site of an p.Y3213C enzyme) without benign variation (NP, NP, NP) PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology

NM_001377.2: Likely PM1 Located in a mutational hot spot and/or critical and well- c.12431C>G Pathogenic established functional domain (e.g., active site of an p.P4144R enzyme) without benign variation (NP, NP, PM2 Absent from controls (or at extremely low frequency if 1.7e-5) recessive) (Table 6) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B849 EYA1 NM_000503.5: Pathogenic PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.951+1G>C, splice sites, initiation codon, single or multiexon splice deletion) in a gene where LOF is a known mechanism of (NP, NP, NP) disease PM2 Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B1162 EYA1 NM_000503.5: Pathogenic PS1 Same amino acid change as a previously established c.1319G>A, pathogenic variant regardless of nucleotide change p.R440Q PS3 Well-established in vitro or in vivo functional studies (NP, NP, NP) supportive of a damaging effect on the gene or gene product PM1 Located in a mutational hot spot and/or critical and well- established functional domain (e.g., active site of an enzyme) without benign variation PM2 Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B664 HNF1B NM_000458.3: Likely PS1 Same amino acid change as a previously established c.494G>A, Pathogenic pathogenic variant regardless of nucleotide change p.R165H PM2 Absent from controls (or at extremely low frequency if (NP, NP, NP) recessive) (Table 6) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B1233 HNF1B NM_000458.3: Likely PM2 Absent from controls (or at extremely low frequency if c.857T>C Pathogenic recessive) (Table 6) in Exome Sequencing Project,1000 p.L286P Genomes Project, or Exome Aggregation Consortium (NP, NP, NP) PM5 Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B284 INF2 NM_022489.3: Pathogenic PS1 Same amino acid change as a previously established c.542T>G, pathogenic variant regardless of nucleotide change p.V181G PM1 Located in a mutational hot spot and/or critical and well- (NP, NP, NP) established functional domain (e.g., active site of an enzyme) without benign variation PM2 Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP1 Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B1137 JAG1 NM_000214.2: Likely PM1 Located in a mutational hot spot and/or critical and well- c.2638T>C, Pathogenic established functional domain (e.g., active site of an p.C880R enzyme) without benign variation (NP, NP, PM2e Absent from controls (or at extremely low frequency if 8.0e-6) recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease Multiple lines of computational evidence support a PP3 deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B848 JAG1 NM_000214.2: Pathogenic PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.2957_2958in splice sites, initiation codon, single or multiexon sTT, p.L986fs deletion) in a gene where LOF is a known mechanism of (NP, NP, NP) disease PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B1142 MYCN NM_005378.5: Likely PS1 Same amino acid change as a previously established c.1178G>A, Pathogenic pathogenic variant regardless of nucleotide change p.R393H PM2 Absent from controls (or at extremely low frequency if (NP, NP, NP) recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B367 NPHP1 Homozygous N/A N/A Deletion B797 NPHP1 Homozygous N/A N/A Deletion B950 NPHP1 Homozygous N/A N/A Deletion B1273 NPHS1 NM_004646.3: PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.139delG splice sites, initiation codon, single or multiexon p.A47Pfs*81 deletion) in a gene where LOF is a known mechanism of (0.0003, NP, disease 1.75e-5) PS1 Same amino acid change as a previously established pathogenic variant regardless of nucleotide change PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology

NM_004646.3: PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.1701C>A splice sites, initiation codon, single or multiexon p.C567* deletion) in a gene where LOF is a known mechanism of (NP, NP, NP) disease PS1 Same amino acid change as a previously established pathogenic variant regardless of nucleotide change PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B144 NPHS1 NM_004646.3: Likely PM1 Located in a mutational hot spot and/or critical and well- c.728C>T Pathogenic established functional domain (e.g., active site of an p.P243L enzyme) without benign variation (NP, NP, NP) PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B801 NPHS1 NM_004646.3: Likely PS1 Same amino acid change as a previously established c.1379G>A Pathogenic pathogenic variant regardless of nucleotide change p.R460E PM2 Absent from controls (or at extremely low frequency if (NP, NP, recessive) in Exome Sequencing Project,1000 Genomes 8.3e-6) Project, or Exome Aggregation Consortium PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B350 NPHS1 NM_004646.3: Pathogenic PS1 Same amino acid change as a previously established c.1868G>T pathogenic variant regardless of nucleotide change p.C623F PS3 Well-established in vitro or in vivo functional studies (0.00015, NP, supportive of a damaging effect on the gene or gene 2.5e-5) product PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B1395 NPHS2 NM_014625.2: Pathogenic PS1 Same amino acid change as a previously established c.503G>A pathogenic variant regardless of nucleotide change p.R168H PS3 Well-established in vitro or in vivo functional studies (NP, NP, supportive of a damaging effect on the gene or gene 8.9e-5) product PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B188 NPHS2 NM_014625.2: Pathogenic PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.855- splice sites, initiation codon, single or multiexon 56AA>del deletion) in a gene where LOF is a known mechanism of p.R286Tfs*17 disease (NP, NP, PS1 Same amino acid change as a previously established 6.9e-5) pathogenic variant regardless of nucleotide change PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B238 NUP93 NM_014669.4: Likely PM2 Absent from controls (or at extremely low frequency if c.575A>G Pathogenic recessive) in Exome Sequencing Project,1000 Genomes p.Y192C Project, or Exome Aggregation Consortium (NP, NP, PP2 Missense variant in a gene that has a low rate of benign 3.3e-5) missense variation and in which missense variants are a common mechanism of disease PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology PP5 Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation B375 PKHD1 NM_138694.3: Pathogenic PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.10452dupT splice sites, initiation codon, single or multiexon p.L3485Sfs*18 deletion) in a gene where LOF is a known mechanism of (NP, NP, disease 8.2e-6) PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology

NM_138694.3: Pathogenic PS1 Same amino acid change as a previously established c.11452G>T pathogenic variant regardless of nucleotide change p.V3818F PM2 Absent from controls (or at extremely low frequency if (NP, NP, NP) recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B354 PLCE1 NM_016341.3: Pathogenic PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.4978_4981d splice sites, initiation codon, single or multiexon elCAGA deletion) in a gene where LOF is a known mechanism of p.Q1660Lfs*9 disease (NP, NP, NP) PS1 Same amino acid change as a previously established pathogenic variant regardless of nucleotide change PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B934 SALL1 NM_002968.2: Pathogenic PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.826C>T, splice sites, initiation codon, single or multiexon p.R276* deletion) in a gene where LOF is a known mechanism of (NP, NP, NP) disease PS1 Same amino acid change as a previously established pathogenic variant regardless of nucleotide change PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B625 TP63 NM_003722.4: Likely PM1 Located in a mutational hot spot and/or critical and well- c.1012C>T, Pathogenic established functional domain (e.g., active site of an p.R338C enzyme) without benign variation (NP, NP, NP) PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B2559 TRPC6 NM_004621.5: Pathogenic PS1 Same amino acid change as a previously established c.2684G>T pathogenic variant regardless of nucleotide change p.R895L PM2 Absent from controls (or at extremely low frequency if (NP, NP, NP) recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PM6 Assumed de novo, but without confirmation of paternity and maternity PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B1873 TTC21B NM_024753.4: Pathogenic PVS1 Null variant (nonsense, frameshift, canonical ±1 or 2 c.986A>T splice sites, initiation codon, single or multiexon p.E329V deletion) in a gene where LOF is a known mechanism of (NP, NP, disease 8.2e-6) PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology

NM_024753.4: Likely PM2 Absent from controls (or at extremely low frequency if c.1038G>A Pathogenic recessive) in Exome Sequencing Project,1000 Genomes p.W346* Project, or Exome Aggregation Consortium (NP, NP, NP) PM3 For recessive disorders, detected in trans with a pathogenic variant PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology B92 WT1 NM_024426.4: Pathogenic PS1 Same amino acid change as a previously established c.1432+4C>T pathogenic variant regardless of nucleotide change Splice PS3 Well-established in vitro or in vivo functional studies (NP, NP, NP) supportive of a damaging effect on the gene or gene product PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project,1000 Genomes Project, or Exome Aggregation Consortium PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology

NP, not present a ACMG classifications according to: Richards, Genet Med 17:405, 2015.32 b Mean allele frequency in NHLBI Exome Sequencing Project (ESP), http://evs.gs.washington.edu/EVS/. c Mean allele frequency in the 1000 Genomes Project, http://www.internationalgenome.org/. d Mean allele frequency in Exome Aggregation Consortium (ExAC), http://exac.broadinstitute.org/. e Although this variant is present once heterozygously in the ExAC database, it is absent in both the 1000 Genomes Project and ESP. Additionally, some resources recommend activating PM2 at a lower threshold for diseases that are either incompletely penetrant or with later-onset disease.33 Reports suggest that the penetrance of Alagille Syndrome caused by JAG1 mutations is around 96% and that up to 30% of JAG1 variant-confirmed relatives of affected probands are asymptomatic.34 Additional support for the pathogenicity of this variant is available from the authors by request.

Supplementary Table 4. Clinical characteristics of probands at BCH who underwent renal transplantation between 2007-2017 compared to patients in the NAPRTCS registry.

Enrolled Probands Total Probands NAPRTCSa Characteristic (2007-2017) (2007-2017) (2007-2014) n = 104 n = 272 n = 2,196 Sex Male 62 (59.6%) 166 (61.0%) 1,270 (57.8%) Female 42 (40.4%) 106 (39.0%) 926 (42.2%) Disease category CAKUT 55 (52.9%) 134 (49.3%) 785 (35.7%) SRNS 21 (20.2%) 39 (14.3%) 327 (14.9%) Chronic glomerulonephritis 7 (6.8%) 36 (13.2%) 301 (13.7%) Renal cystic ciliopathy 9 (8.6%) 19 (7.0%) 133 (6.1%) Nephrolithiasis 3 (2.9%) 4 (1.5%) 52 (2.4%) ESRD of unknown etiology 9 (8.6%) 17 (6.3%) 144 (6.6%) Other (non-intrinsic renal) b --- 23 (8.4%) 454 (20.6%) Extra-renal manifestations Present 55 (52.9%) 143 (52.6%) Absent 49 (47.1%) 129 (47.4%) Family Structure c Consanguineous 9 (8.7%) --- Positive family history 23 (22.1%) --- Kidney donor type d Deceased donor 49 (45.4%) 138 (48.8%) Living related donor 49 (45.4%) 117 (41.3%) Living unrelated donor 10 (9.2%) 28 (9.9%)

CAKUT, congenital anomalies of the kidney and urinary tract; ESRD, end-stage renal disease; SRNS, steroid resistant nephrotic syndrome a Data for 2007-2014 were obtained by subtracting the numbers from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCs) 2006 and 2014 annual reports, https://web.emmes.com/study/ped/annlrept/annlrept2006.pdf, https://web.emmes.com/study/ped/annlrept/annualrept2014.pdf. b Includes ESRD secondary to septic shock, drug toxicity, renal infarct, systemic immunologic disease, sickle cell nephropathy, diabetic glomerulonephritis, or other non-intrinsic renal disease. c Family history for enrolled probands was obtained via a research-based clinical questionnaire. Reliable family history was unable to be obtained for many patients who were not enrolled. d Total number of donors exceeds the number of probands as several patients had multiple renal transplants between 2007-2017 at Boston Children’s Hospital. Supplementary Table 5. Clinical consequences following establishment of a molecular genetic diagnosis for 21 genes identified in 104 families. Table is sorted alphabetically by gene symbol within the 5 diagnostic groups and color coded as in Table 1 and Figure 1.

Molecular Clinical Consequences Gene Diagnosis Genetic Pre-Transplant Post-Transplant (OMIM #)a Extrarenal Manifestations Counseling Management Management • Failure to thrive • Microcephaly • Cleft lip/palate Wolf- • GI malrotation • Screening for and 4p16.3 Hirschhorn  (AD) • Genital anomalies management of extra- deletion Syndrome • renal manifestations (# 194190) Scoliosis, polydactyly, fused vertebrae • Hydrocephalus • Seizures • MODY diabetes • • Subclinical elevated LFTs Consideration of a steroid HNF1B/ Renal Cysts minimization • Neonatal cholestasis • Screening for and TCF1 and Diabetes immunosuppression  (AD) • Genital tract anomalies management of extra- (17q12 Syndrome protocol and avoidance of • Hyperuricemia renal manifestations deletion) (# 137920) pro-diabetogenic drugs • Hypomagnesemia when possible • Learning difficulties • Hearing loss Branchio-Oto- • Preauricular pits • Screening for and Renal EYA1  (AD) • External ear/cochlear management of extra- Syndrome renal manifestations (# 113650) malformations • Branchial cleft fistulas or cysts • Eye disease • Cardiac defects • Liver disease Alagille • Screening for and • Vertebral anomalies JAG1 Syndrome  (AD) management of extra- • Vascular disease (# 118450) renal manifestations • Increased risk hepatocellular and papillary thyroid cancer • Mild learning disabilities • Cardiac defects Feingold • Duodenal/esophageal atresia • Screening for and MYCN Syndrome  (AD) • Vocal cord paralysis management of extra- (# 164280) • Asplenia renal manifestations • Learning difficulties • Hearing loss • External ear anomalies Townes- • Eye anomalies • Screening for and Brocks • Cardiac defects SALL1  (AD) management of extra- Syndrome • Anorectal malformations renal manifestations (# 107480) • Hypospadias, cryptorchidism • Broad thumb, polydactyly, syndactyly • Hearing loss • Blepharitis, dacrocystitis, xerostomia Ectrodactyly, • Microdontia ectodermal • Choanal atresia • Screening for and dysplasia, and • Cryptorchidism TP63  (AD) management of extra- cleft lip/palate • Syndactyly, ecterodactyly renal manifestations syndrome 3 • Hyperkeratosis (# 604292) • Dystrophic and pitted nails • Sparse, thin hair • Hypogonadotropic hypogonadism SRNS; Expect no response of Charcot- SRNS to steroids and INF2 Marie-Tooth  (AD) • Peripheral neuropathy reduced response to IIT. Disease No need for renal biopsy. (# 613237, # 614455) CNS INF2: Consideration of a steroid NPHS1 (AR) • None reported minimization protocol given (# 256300) • Screening for the reduced risk of disease neuropathy CNS  recurrence from ~33% to NPHS2 (AR) • None reported • Consider genetic testing (# 600995) ~8% when a genetic prior to LRD given AD SRNS mutation is identified.10,44 NUP93  (AR) • None reported inheritance (# 616892)

CNS PLCE1  (AR) • None reported PLCE1: (# 610725) NPHS1: • Rare reports of children SRNS • Monitor for FSGS TRPC6  (AD) • None reported who do respond to (# 603965) recurrence if Fin(major) steroid therapy allele (c.121delCT) due to

formation of anti-nephrin Frasier WT1: antibodies.47 Syndrome; • Depending on particular • Prophylactic

Denys-Drash allele: gonadectomy and native  WT1 Syndrome (AD) -Gonadoblastoma nephrectomies in certain (# 136680, -XY gonadal dysgenesis situations # 194080, • Ambiguous genitalia • Consider genetic testing # 256370) prior to LRD given AD inheritance • Monitor for proteinuria • ACE inhibitors can delay Alport and hematuria given rare • Cataracts, myopia progression to ESRD COL4A5 Syndrome  (XD) reports of anti-GBM • Hearing loss • Consider genetic testing (# 301050) nephritis post-transplant prior to LRD (~1-5% of patients) • Retinitis pigmentosa • Strabismus • Screening for and NPHP • Liver disease (cholestasis, • Minimize exposure to CEP83  (AR) management of extra- (# 615862) liver fibrosis) hepatotoxic medications renal manifestations • Hydrocephalus • Developmental delay • Retinal dystrophy • Cleft lip/palate • Cardiac defects • Screening for and Short-rib • Restrictive disease management of extra- Thoracic DYNC2H1  (AR) • Biliary dysplasia renal manifestations Dysplasia • • (# 613091) Intestinal malrotation Optimization of • Anal atresia respiratory status • Scoliosis • Skeletal anomalies

• Retinitis pigmentosa • Higher rate of post- NPHP • Oculomotor apraxia • Screening for and NPHP1 (# 256100, transplant polyuria in  (AR) • Developmental delay management of extra- deletion # 266900, patients with native # 609583) • Ataxia and impaired balance renal manifestations • Cerebellar vermis hypoplasia kidneys

• Consideration of a liver- Autosomal • Liver fibrosis, portal kidney transplant Recessive , and hepatic Polycystic • Screening for and • Minimize exposure to PKHD1  (AR) cysts management of extra- hepatotoxic medications Kidney • Increased risk for cholangitis Disease renal manifestations, • Pancreatic cysts (# 263200) especially liver disease NPHP; • Short stature Short-rib • Screening for and • Hepatic cysts TTC21B Thoracic  (AR) management of extra- • Scoliosis Dysplasia renal manifestations (# 613820, • Polydactyly # 613819) • Consider hemodialysis in • Trial of pyridoxine the post-operative period • Retinopathy • 5-6x/week dialysis prior for patients with systemic • block to transplant to bring involvement and limited Primary • PVD down oxalate levels urine output45 Hyperoxaluria AGXT  (AR) • Osteosclerosis, bone pain, • Timely listing for • Slow resolubilization of type 1 (# 259900) pathologic fractures transplantation prior to systemic calcium oxalate • Calcinosis cutis metastatica systemic oxalosis may jeopardize graft • Peripheral neuropathy • Combined liver-kidney function, need to optimize transplant is essential fluids and consider use of crystallization inhibitors45

ACE, angiotensin-converting enzyme; AD, autosomal dominant; AR, autosomal recessive; ARPKD, autosomal recessive polycystic kidney disease; BOR, branchio-oto-renal syndrome; CNS, congenital nephrotic syndrome; ESRD, end-stage renal disease; FSGS, focal segmental glomerulosclerosis; GI, gastrointestinal; IIT, intensive immunosuppression therapy; IS, immunosuppression; LFTs, liver function tests; LRD, living related donation; MODY, mature onset diabetes of the young; NPHP, nephronophthisis; PVD, peripheral vascular disease; SRNS, steroid resistant nephrotic syndrome; XD, x-linked dominant

a OMIM: Online Mendelian Inheritance in Man, https://www.omim.org

Renal transplant recipients at Boston Children’s Hospital between 2007-2017 272 probands

Enrolled Not Enrolled 104 individuals (38.2%) 168 individuals (61.8%)

Excluded for Medical Reasons* (n=23)

Whole Exome Sequencing (WES) Transitioned Care** (n=104) (n=41)

Unable to Consent*** (n=18) Consanguineous Non-Consanguineous (n=9) (n=95) Deceased (n=2) Declined (n=45) 6/9 28/95 individuals individuals To Be Recruited with causative with causative (n=39) mutation mutation detected in detected in CKD gene CKD gene

Molecular Molecular diagnosis in diagnosis in 66.7% 29.5%

Supplementary Figure 1: Recruitment strategy and likelihood of detecting a monogenic cause of CKD in 104 renal transplant recipients.

272 probands who were diagnosed with CKD before 25 years of age received a renal transplant within a continuous 10-year period between 2007-2017 at Boston Children’s Hospital. We enrolled 104 individuals for whole exome sequencing (WES). 168 individuals were not enrolled for the reasons shown. A likely causative mutation was identified in 66.7% of patients with reported consanguinity and in 29.5% of patients without consanguinity.

* CKD due to non-intrinsic renal disease (e.g. septic shock, calcineurin inhibitor toxicity) ** Family moved away or patient transitioned to adult care *** Developmentally delayed adult or guardianship issues that prevented informed consent (i) Keep rare SNPs (MAF<1%)

(ii) Keep non-synonymous and splice site variants

Evaluate for known genes (iii) in each clinical category for CKD (Suppl. Table 1a-g)

Keep variants that are likely (iv) deleterious for protein function by established criteria

Phenotype match, segregation (v) analysis based on pedigree structure, and literature review

Accept causative mutations in known CKD genes

Supplementary Figure 2: Variant filtering process for the identification of causative mutations in genes known to cause chronic kidney disease.

Schematic overview of the workflow that was used for filtering of WES data in all families. i) Keep rare variants that are present with a minor allele frequency (MAF) <1% in healthy control cohorts (ESP, ExAC, gnomAD, 1000 Genomes Project). ii) Keep non-synonymous variants and intronic variants that are located within splice sites. iii) Apply known gene approach by selecting all variants detected in known genes for each clinical CKD disease category. For patients with ESRD of unknown etiology, analyses were performed for all genes known to cause chronic kidney disease. iv) Rank remaining variants based on their predicted likelihoods of being deleterious for the function of the encoded protein. Variants that were protein-truncating (nonsense, frameshift, obligatory splice, or loss of start or stop codons), highly conserved across phylogeny, predicted to be deleterious based on at least two of three prediction programs (PoyPhen2, SIFT, and MutationTaster), previously reported as disease causing, or with loss of function supported by functional data were kept. v) Review literature and delineate whether the detected mutation matches the patient’s phenotype. When parental DNA was available, segregation analysis was performed to ensure that variants fit with the pedigree structure. Supplementary Figure 3: Percentage of patients with a molecular genetic diagnosis varies by clinical diagnostic group.

The six clinical diagnostic groups are ordered from left to right by the likelihood of establishing a molecular genetic diagnosis. The percentages in each bar represent the fraction of patients in each clinical diagnostic group in whom a molecular diagnosis was established.

Three patients with urinary stone disease were clinically diagnosed with primary hyperoxaluria type 1, and all three patients had mutations in AGXT. Seven of 9 (78%) patients with a renal cystic ciliopathy had an underlying genetic mutation in 5 different genes. 4/9 (44%) patients with ESRD of unknown etiology had a mutation in 4 different genes. 9/21 (43%) of patients with SRNS had a molecular diagnosis in 5 different genes. 10/55 (18%) patients with CAKUT had a mutation in 6 different genes and 2 CNVs. One patient with chronic glomerulonephritis had a mutation in COL4A5.

CAKUT, congenital anomalies of the kidney and urinary tract; ESRD, end-stage renal disease; GN, glomerulonephritis; SRNS, steroid resistant nephrotic syndrome. A) B) 100 100

80 80 67% (6/9)

60 60 45% (25/55)

40 30% 40

(28/95) Diagnosis (%) Diagnosis Diagnosis (%) Diagnosis 18% (9/49) 20

Patients with awithMolecular Patients 20 Patients with awithMolecular Patients

0 0 Consanguineous Non-Consanguineous Syndromic Isolated

C) 100

80

60 48% (11/23)

40 28%

(23/81) Diagnosis (%) Diagnosis

20 Patients with awithMolecular Patients

0 Family History No Family History

Supplementary Figure 4. The likelihood of identifying a molecular diagnosis is higher when there is consanguinity, extra-renal manifestations, or a positive family history.

A) Nine families in our cohort reported a history of consanguinity. Amongst these families, 6/9 (67%) were found to have a causative mutation in a known CKD gene. 28/95 (30%) of families with no reported consanguinity were molecularly solved. B) 55/104 patients had extra-renal symptoms. We detected an underlying molecular diagnosis in 25 of these patients (45%). Only 9/49 (18%) patients with isolated kidney disease had a genetic diagnosis. C) Similarly, 11/23 (48%) patients with a family history of kidney disease had a molecular diagnosis, compared to 23/81 (28%) of patients without a positive family history. A) ACA GAA CTT AAG TGG TAT Thr Glu Leu Lys Trp Tyr Father

WT/WT p.E328V/WT WT/WT WT/WT ACA GA/TA CTT AAG TGG TAT Thr Glu/Val Leu Lys Trp Tyr Mother

ACA GA/TA CTT AAG TGG/A TAT p.E328V/WT WT/p.W346* Thr Glu/Val Leu Lys STOP Tyr Proband

B) chr2:166786731C>T chr2:166786783T>A c.1038G>A c.986A>T p.Trp346* p.Glu329Val

Supplementary Figure 5. TTC21B compound heterozygous alleles are inherited in trans in for patient B1873.

A) Sanger sequencing confirming the c.986A>T and c.1038G>A alleles in TTC21B. The proband is heterozygous for both alleles, mother is heterozygous for c.986A>T, and the father is wild type for both alleles. B) Further inspection of the raw exome sequencing data demonstrate that the two alleles are on different DNA strands, confirming that they were inherited in trans.