Table 2.

Information on identified mutations in congenital anomalies of the kidney and urinary tract genes known to cause isolated or syndromic congenital anomalies of the kidney and urinary tract or mutations in genes known to phenocopy congenital anomalies of the kidney and urinary tract and the corresponding clinical phenotype

Family IdentificationaGeneMode of TransmissionNucleotide ChangeAmino Acid ChangeStateEvolutionary ConservationbPP2 SIFT MTCADD ScoreEVScgnomADcACMGdHGMDePhenotypesSegregation
A617fSALL1gDominantc.703G>Ap.Ala 235ThrHetDanio rerio0.782 Del. D.C.18/0/3/277166Likely pathogenicDMTownes Brock syndromeVariant inherited from father (affection status unknown)
BL VUR R duplex
A1041hSRGAP1gDominantc.1993C>Ap.Pro 665ThrHetCaenorhabditis elegans0.309 Del. D.C.24//PathogenicDML horseshoe kidneyVariant inherited from mother (affection status unknown)
Cleft palate
Intellectual disability
A1147GATA3gDe novo dominantc.708_709 insTp.Ser 237Glnfs*67iHet/NA//PathogenicGeneBL VURDe novo variant (paternity and maternity confirmed)
Septate uterus
Hearing loss
Progressive renal impairment
A1160jTrisomy 20pgDe novo//L RADe novo variant (paternity and maternity confirmed)
Mitral regurgitation
Intellectual disability
A3346kTRPS1gDominantc.2795C>Tp.Ala 932ValHetSaccharomyces cerevisiae0.997 Del. D.C.21//Likely pathogenicDMTrichorhinophalangeal syndromeVariant inherited from affected father (trichorhinophalangeal syndrome)
A4450KMT2DgDominantc.6638G>Ap.Gly2213AspHetXenopus tropicalis0.186 Tol. D.C.40/1/40850/6/171078Likely pathogenicDMBL VURVariant inherited from father (mild facial dysmorphism)
Cleft palate
Facial dysmorphism
Protruding ears
Delayed development
A4478lFAT4gCompound hetc.9279A>Cp.Gln3093HisHetD. rerioTol. D.C.16/0/10/244826Likely pathogenicDML RA, R UVJOYes (unaffected parents het carriers, variant confirmed in affected siblings)
FAT4gc.9313A>Gp.Ser3105GlyHetXenopus tropicalisTol .D.C.4/0/5/245198Facial dysmorphism
Psychomotor delay
Intellectual disability
Sprengel deformity
Other skeletal deformities
BL cryptorchism
A4672f,mHNF1BgDominantc.1024T>Cp.Ser 342ProHetD. rerio0.767 Del. D.C.8/0/1/243686Likely pathogenicDMR RHDVariant inherited from mother (affection status unknown)
A4732hSRGAP1gDominantc.806G>Ap.Cys 269TyrHetD. rerio0.840 Tol. D.C.25//PathogenicDMR MCDKVariant inherited from affected mother (R duplicated kidney)
R ureterocele
A3403nTRAP1gRecessivec.1406G>Ap.Arg 469HisHomS. cerevisiaeo0.997 Del. D.C.330/66/423411/1552/269946PathogenicDMBL VURYes (unaffected parents het carriers, variant segregates in two affected siblings)
A3880pTBX18gDominantc.1010delGp.Gly 337Val fs*19iHet/NA//Likely pathogenicDMUPJOYes (segregates in multiple affected family members)
HAGqNRIP1gDominantc.279delp.Trp 93* (stop gain)iHet/NA//Likely pathogenicDMRHDYes (segregates in multiple affected family members)
A1023rFREM2gCompound hetc.4031G>Ap.Arg 1344HisHetD. rerio0.085 Del./160/23/427712/102/277164Uncertain significanceDMR RANA
FREM2gc.7535G>Ap.Arg 2512HisHetD. rerio0.929 Del./180/10/42900/132/276840Uncertain significanceDMBladder calculi
A1220fROBO2gDominantc.292G>Tp.Gly 98TrpHetC. elegans0.880 Del. D.C.19//Uncertain significanceDMR UPJONA
Renal stones
A1232rFREM2gCompound hetc.649C>Tp.Arg 217CysHetX. tropicalis0.836 Del./17/0/1/244270Uncertain significanceDMPUV, R VUR, L UPJONA
FREM2gc.4031G>Ap.Arg 1344HisHetD. rerio0.085 Del./160/23/427712/102/277164Uncertain significanceDMProgressive renal impairment
B24sETV4gRecessivec.1244G>Ap.Arg 415HisHomDrosphilia melanogaster1.00 Del. D.C.360/1/42990/23/245730Likely pathogenicGeneR VURVariant het in unaffected mother, paternal DNA NA
B196CTU2gRecessivec.1399C>Tp.Arg 467CysHomD. melanogastert0.926 Del. D.C.21/0/1/245354Likely pathogenicGeneL hydronephrosisVariant het in unaffected mother, paternal DNA NA
Facial dysmorphism
Intellectual disability
Growth retardation
Pulmonary stenosis
Imperforate anus
Absent uterus
B268uHPSE2gRecessivec.457C>Tp.Arg 153*iHom/10/0/3/245274PathogenicDMUrofacial syndromeNA
A3837TBX18gDominantc.1802A>Gp.Gln 601ArgHetCiona intestinalis0.932 Del. D.C.14/0/4/217866Uncertain significanceGenePUV, BL VURNA
A3900FRAS1gCompound hetc.3998T>Cp.Val 1333AlaHetC. elegansv0.086 Tol. D.C.15/0/12/244984Uncertain significanceGenePUVNA
FRAS1gc.8131T>Cp.Tyr 2711HisHetC. elegans0.928 Del. D.C.13/1/29/191356Uncertain significanceGene
B211Trisomy 18gDe novo dominant//R MCDK, L RHDNA
Facial dysmorphism
Short palpebral fissures
Very small low-set ears
High arched palate
Congenital cardiopathy
Esophageal atresia and trachoesophageal fistula
High position of the anus
Generalized nail hypoplasia
Syndactyly of the feet
B630HNF1BgDominant1.5-Mb deletion chromosome 17q12PathogenicDMBL MCDKNA
Hyperuricemia ADHD
Developmental delay
B1434CTU2gRecessivec.1399C>Tp.Arg 467CysHomD. melanogasterw0.926 Del. D.C.21/0/1/245354Likely pathogenicGeneR MCDK, L hydronephrosisNA
Global developmental delay
Brain MRI; cave of septum pellucidium
B1435ACTG1gDe novoc.464C>Tp.Ser 155PheHetS. cerevisiae1.00 Del. D.C.18//PathogenicDML partial duplex kidney, L hydroureter, L hydronephrosis,NA
Facial dysmorphism, lissencephaly, Dany–Walker malformation, global developmental delay
Growth retardation
B1439SALL1gDominantc.1666G>Ap.Gly 556SerHetD. rerio0.999 Del. D.C.20/0/3/245992Uncertain significanceGeneBL VUR, BL hydronephrosisNA
B1316GREB1LgDominantc.4276G>Ap.Val 1426IleHetD. rerioy0.079 Tol. D.C.14//Likely pathogenicGeneBL RHDNA
Facial dysmorphism
Short neck
Single transverse palmar crease
A1261xGREB1LgDominantc.5068G>Ap.Val1690MetHetX. tropicalis0.681 Del. D.C.30//Likely pathogenicGeneBL VURYes (segregates in multiple affected family members)
Supernumerary nipple
F1436KAT6BgDominant/de novoc.4285G>Ap.Glu1429LysHetD. rerio0.995 Tol. D.C.8//Likely pathogenicGeneBL VUR, BL RHDNA
Facial dysmorphism
Developmental delay
Dysplastic ears
Muscle weakness (pectoralis and trapezius with limited mobility of shoulder)
B1650HPSE2gRecessivec.1099–2A>G100% ESSHom/NA//PathogenicGeneUrofacial syndrome “inverted smile”Yes (unaffected parents het carriers, variant segregates in two affected siblings)
Hinman syndrome
A3962NPHP1zRecessivec.1804delAp.Ser 602Val fs*4iHom/NA/0/1/245974PathogenicGeneBL RHDNA
A4235TMEM 231zRecessivec.119T>Gp.Leu40ArgHomC. elegans0.951 Del. D.C.23//Likely pathogenicGeneBL RHD, Facial dysmorphism, microcephaly, intellectual disability, polysyndactyly, heart anomalies, growth retardation.Yes (segregates in two affected family members)
B1306NPHP4zCompound hetc.3983C>Tp.Pro1328LeuHetC. elegans0.999 Del. /260/4/20470/62/268266Likely pathogenicGeneBL RHDNA
NPHP4zc.2021G>Ap.Arg674HisHetC. elegans0.999 Del. /290/1/20890/8/277216Likely pathogenicGeneGrowth retardation
Patent ductus arteriosus
Facial dysmorphism
  • PP2, PolyPhen 2; SIFT, Sorting Intolerant from Tolerant; MT, Mutation Taster; CADD, Combined Annotation Dependent Depletion; EVS, Exome Variant Server; gnomAD, Genome Aggregation Database; ACMG, American College of Medical Genetics; Het, heterozygous; Del., deleterious; D.C., disease causing; /, data not available; DM, disease mutation; BL, bilateral; VUR, vesicoureteric reflux; R, right; L, left; MCDK, multicystic dysplastic kidney; —, not applicable; NA, not available; RA, renal agenesis; RHD, renal/hypodysplasia; Tol., tolerated; UVJO, ureterovesical junction obstruction; Hom, homozygous; UPJO, ureteropelvic junction obstruction; PUV, posterior urethral valve; ADHD, Attention Deficit Hyperactivity Disorder; Mb, megabase; MRI, magnetic resonance imaging; ESS, essential splice site.

  • a For families in which the disease-causing variant has previously been reported in the literature, the corresponding reference is provided.

  • b Evolutionary conservation was assessed across phylogeny over eight species: Mus musculus, Gallus gallus, Xenopus tropicalis, Danio rerio, Caenorhabditis elegans, Ciona intestinalis, Drosphilia melanogaster, and Saccharomyces cerevisiae. If conservation is interrupted in one species but otherwise preserved across phylogeny, additional information is provided.

  • c Variant frequencies listed for homozygous/hemizygous (if applicable)/heterozygous/total alleles detected in the population.

  • d ACMG American College of Human Genetics Standards and Guidelines Classification as pathogenic, likely pathogenic, or uncertain significance.66

  • e HGMD, Human Gene Mutation Database; ( If the exact variant has previously been reported and classified as a pathogenic mutation that is disease causing, the variant is denoted as DM. If the gene but not the exact variant has been reported for the corresponding phenotype, gene is indicated.

  • f Ref. 42.

  • g Mutations in the isolated or syndromic gene identified in families with the corresponding phenotype.

  • h Ref. 21.

  • i Frameshift, stop loss, stop gain, or nonsense variant.

  • j Ref. 64.

  • k Ref. 68.

  • l Ref. 69.

  • m Finding in more than two categories.

  • n Ref. 36.

  • o Interruption in conservation due to leucine present in C. intestinalis.

  • p Ref. 23.

  • q Ref. 43.

  • r Ref. 33.

  • s Ref. 32.

  • t Interruption in conservation due to serine present in C. elegans.

  • u Ref. 46.

  • v Interruption in conservation due to arginine present in D. rerio.

  • w Interruption in conservation due to serine present in C. elegans.

  • x Ref. 44.

  • y Interruption in conservation due to methionine present in M. musculus.

  • z Mutations in phenocopy gene.