Supplemental Table 1. Multiorgan syndromes associated with CAKUT in humans

Syndrome MOI Gene Extrarenal phenotype Renal phenotype References
Alagille AD JAGGED1 Intrahepatic cholestasis Cystic dysplasia 122
abnormalities of heart, eyes
and vertebrae
Apert AD FGFR2 Craniosynostosis, syndactyly Hydronephrosis 123
Beckwith- AD p57KIP2 Macroglossia, gigantism, Medullary dysplasia 52
Wiedemann visceromegaly Wilms’ tumor
Branchio-oto- AD Eya1 Deafness, ear malformations, Unilateral or bilateral 57, 124
Renal Six1 branchial cysts renal agenesis, VUR
Six5 renal hypodysplasia
Campomelic AD Sox9 Short and bowed femora and Hydroureter, renal 125, 126
dysplasia tibiae, hypoplastic vertebrae hypodysplasia,
cranial anomalies, heart defects hydronephrosis
Fraser AR Fras1 Cryptophthalmos, syndactyly Renal agenesis, dysplasia 127
ear and heart defects
HDR AD Gata3 Hypoparathyroidism Renal dysplasia 128, 129
sensorineural deafness
Jeune AR Ift80 Skeletal dysplasia with small Cystic kidney disease 130
thorax
Kallman XL Kal1 Anosmia, hypogonadotrophic Renal agenesis 131, 132
hypogonadism
Mammary- AD Tbx3 Posterior limb deficiencies Renal dysplasia 133
ulnar hypoplastic teeth and breasts
delayed pubertal development
Okihiro AD Sall4 Limb, anorectal, ear, heart, eye Renal agenesis, VUR 134
movement abnormalities cross-fused ectopia
Pallister-Hall AD Gli3 Polysyndactyly, hypothalamic Renal dysplasia 135
hamartoma, tracheal stenosis
imperforate anus
Renal-coloboma AD Pax2 Optic nerve coloboma Renal hypoplasia, VUR 136
hearing loss
Renal tubular AR AGT Oligohydramnios, facial Tubular dysplasia 111
dysgenesis Renin dysmorphia, arthrogryposis
ACE lung hypoplasia, skull
AT1R ossification defect
Renal cysts AD HNF1β MODY, genital anomalies Glomerulocystic kidney 137
and diabetes disease, MCDK, uni- or
bilateral cystic kidneys
renal hypodysplasia
horseshoe kidney
oligomeganephronia
Rubenstein- AD Crebbp Mental retardation, heart defects Renal hypolasia 138
Taybi broad thumbs and toes
Simpson-Golabi- XL Gpc3 Somatic overgrowth, tumors Medullary dysplasia 139
Behmel
Smitz-Lemni- AR 7-HCR Microcephaly, mental retardation Renal agenesis, dysplasia 140
Opitz micrognathia, ptosis of eyelids
poly/syndatyly, cataracts
heart defects
Townes-Brock AD Sall1 Anal atresia, sensorineural Renal hypodysplasia, VUR 141
hearing loss, triphalangeal
thumbs
Zellweger AR Pex1 Dysmorphic facial features Cystic dysplasia, VUR 142
neurologic dysfunction

AD- autosomal dominant, AR- autosomal recessive, XL- X-linked, MODY- maturity-onset diabetes of the young, MCDK- multicystic dysplastic kidney, VUR- vesico-ureteral reflux. Please see Supplemental Table 2 for glossary of genes.

References:

122. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome.Nat Genet 16:235-242

123. Wilkie AO, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, Hayward RD, David DJ, Pulleyn LJ, Rutland P, MalcolmS, WinterRM, Reardon W (1995) Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.Nat Genet 9:165-172

124. Kochhar A, Fischer SM, Kimberling WJ, Smith RJ (2007) Branchio-oto-renal syndrome. Am J Med Genet 143:1671-1678

125. Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, Pasantes J, Bricarelli FD, Keutel J, Hustert E (1994) Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.Cell 79:1111-1120

126. Houston CS, Opitz JM, Spranger JW, Macpherson RI, Reed MH, Gilbert EF, Herrmann J, Schinzel A (1983) The campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17-year-old boy first reported by Maroteaux et al in 1971.Am J Med Genet 15:3-28

127. McGregor L, Makela V, Darling SM, Vrontou S, Chalepakis G, Roberts C, Smart N, Rutland P, Prescott N, Hopkins J, Bentley E, Shaw A, Roberts E, Mueller R, Jadeja S, Philip N, Nelson J, Francannet C, Perez-Aytes A, Megarbane A, Kerr B, Wainwright B, Woolf AS, Winter RM, Scambler PJ (2003) Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein.Nat Genet 34:203-208

128. Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, Harding B, Beetz R, Bilous RW, Holdaway I, Shaw NJ, Fryns JP, Van de Ven W, Thakker RV, Devriendt K (2000) GATA3 haplo-insufficiency causes human HDR syndrome. Nature 406:419-422

129. Muroya K, Hasegawa T, Ito Y, Nagai T, Isotani H, Iwata Y, Yamamoto K, Fujimoto S, Seishu S, Fukushima Y, Hasegawa Y, Ogata T (2001) GATA3 abnormalities and the phenotypic spectrum of HDR syndrome.J Med Genet 38:374-380

130. Beales PL, Bland E, Tobin JL, Bacchelli C, Tuysuz B, Hill J, Rix S, Pearson CG, Kai M, Hartley J, Johnson C, Irving M, Elcioglu N, Winey M, Tada M, Scambler PJ (2007) IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy.Nat Genet 39:727-729

131. Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, Carrozzo R, Maestrini E, Pieretti M, Taillon-Miller P (1991) A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules.Nature 353:529-536

132. Duke V, Quinton R, Gordon I, Bouloux PM, Woolf AS (1998) Proteinuria, hypertension and chronic renal failure in X-linked Kallmann's syndrome, a defined genetic cause of solitary functioning kidney.Nephrol Dial Transplant 13:1998-2003

133. Bamshad M, Lin RC, Law DJ, Watkins WC, Krakowiak PA, Moore ME, Franceschini P, Lala R, Holmes LB, Gebuhr TC, Bruneau BG, Schinzel A, Seidman JG, Seidman CE, Jorde LB (1997) Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome.Nat Genet 16:311-315

134. Sakaki-Yumoto M, Kobayashi C, Sato A, Fujimura S, Matsumoto Y, Takasato M, Kodama T, Aburatani H, Asashima M, Yoshida N, Nishinakamura R (2006) The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development. Development 133:3005-3013

135. Kang S, Graham JM Jr, Olney AH, Biesecker LG (1997) GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome.Nat Genet 15:266-268

136. Sanyanusin P, Schimmenti LA, McNoe LA, Ward TA, Pierpont ME, Sullivan MJ, Dobyns WB, Eccles MR (1995) Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux.Nat Genet 9:358-364

137. Bohn S, Thomas H, Turan G, Ellard S, Bingham C, Hattersley AT, Ryffel GU (2003) Distinct molecular and morphogenetic properties of mutations in the human HNF1beta gene that lead to defective kidney development.J Am Soc Nephrol 14:2033-2041

138. Kanjilal D, Basir MA, Verma RS, Rajegowda BK, Lala R, Nagaraj A (1992) New dysmorphic features in Rubinstein-Taybi syndrome. J Med Genet 29:669-670

139. Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D (1996) Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome.Nat Genet 12:241-247

140. Tint GS, Irons M, Elias ER, Batta AK, Frieden R, Chen TS, Salen G (1994) Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome.N Engl J Med 330:107-113

141. Kohlhase J, Wischermann A, Reichenbach H, Froster U, Engel W (1998) Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome.Nat Genet 18:81-83

142. Preuss N, Brosius U, Biermanns M, Muntau AC, Conzelmann E, Gartner J (2002) PEX1 mutations in complementation group 1 of Zellweger spectrum patients correlate with severity of disease.Pediatr Res 51:706-714