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. 2018 Aug 24;29(9):2348–2361. doi: 10.1681/ASN.2017121265

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 Identificationa Gene Mode of Transmission Nucleotide Change Amino Acid Change State Evolutionary Conservationb PP2 SIFT MT CADD Score EVSc gnomADc ACMGd HGMDe Phenotypes Segregation
A617f SALL1g Dominant c.703G>A p.Ala 235Thr Het Danio rerio 0.782 Del. D.C. 18 / 0/3/277166 Likely pathogenic DM Townes Brock syndrome Variant inherited from father (affection status unknown)
BL VUR R duplex
A1041h SRGAP1g Dominant c.1993C>A p.Pro 665Thr Het Caenorhabditis elegans 0.309 Del. D.C. 24 / / Pathogenic DM L horseshoe kidney Variant inherited from mother (affection status unknown)
R MCDK
Cleft palate
Intellectual disability
A1147 GATA3g De novo dominant c.708_709 insT p.Ser 237Glnfs*67i Het — / NA / / Pathogenic Gene BL VUR De novo variant (paternity and maternity confirmed)
Septate uterus
Hearing loss
Progressive renal impairment
A1160j Trisomy 20pg De novo — / / L RA De novo variant (paternity and maternity confirmed)
Mitral regurgitation
Hypotonia
Intellectual disability
A3346k TRPS1g Dominant c.2795C>T p.Ala 932Val Het Saccharomyces cerevisiae 0.997 Del. D.C. 21 / / Likely pathogenic DM Trichorhinophalangeal syndrome Variant inherited from affected father (trichorhinophalangeal syndrome)
BL RHD, VUR
A4450 KMT2Dg Dominant c.6638G>A p.Gly2213Asp Het Xenopus tropicalis 0.186 Tol. D.C. 4 0/1/4085 0/6/171078 Likely pathogenic DM BL VUR Variant inherited from father (mild facial dysmorphism)
Cleft palate
Facial dysmorphism
Protruding ears
Delayed development
A4478l FAT4g Compound het c.9279A>C p.Gln3093His Het D. rerio Tol. D.C. 16 / 0/10/244826 Likely pathogenic DM L RA, R UVJO Yes (unaffected parents het carriers, variant confirmed in affected siblings)
FAT4g c.9313A>G p.Ser3105Gly Het Xenopus tropicalis Tol .D.C. 4 / 0/5/245198 Facial dysmorphism
Psychomotor delay
Intellectual disability
Hypotonia
Sprengel deformity
Other skeletal deformities
BL cryptorchism
A4672f,m HNF1Bg Dominant c.1024T>C p.Ser 342Pro Het D. rerio 0.767 Del. D.C. 8 / 0/1/243686 Likely pathogenic DM R RHD Variant inherited from mother (affection status unknown)
Cystinuria
A4732h SRGAP1g Dominant c.806G>A p.Cys 269Tyr Het D. rerio 0.840 Tol. D.C. 25 / / Pathogenic DM R MCDK Variant inherited from affected mother (R duplicated kidney)
R ureterocele
A3403n TRAP1g Recessive c.1406G>A p.Arg 469His Hom S. cerevisiaeo 0.997 Del. D.C. 33 0/66/4234 11/1552/269946 Pathogenic DM BL VUR Yes (unaffected parents het carriers, variant segregates in two affected siblings)
A3880p TBX18g Dominant c.1010delG p.Gly 337Val fs*19i Het — / NA / / Likely pathogenic DM UPJO Yes (segregates in multiple affected family members)
HAGq NRIP1g Dominant c.279del p.Trp 93* (stop gain)i Het — / NA / / Likely pathogenic DM RHD Yes (segregates in multiple affected family members)
MCDK
Hydronephrosis
A1023r FREM2g Compound het c.4031G>A p.Arg 1344His Het D. rerio 0.085 Del./ 16 0/23/4277 12/102/277164 Uncertain significance DM R RA NA
FREM2g c.7535G>A p.Arg 2512His Het D. rerio 0.929 Del./ 18 0/10/4290 0/132/276840 Uncertain significance DM Bladder calculi
A1220f ROBO2g Dominant c.292G>T p.Gly 98Trp Het C. elegans 0.880 Del. D.C. 19 / / Uncertain significance DM R UPJO NA
Renal stones
A1232r FREM2g Compound het c.649C>T p.Arg 217Cys Het X. tropicalis 0.836 Del./ 17 / 0/1/244270 Uncertain significance DM PUV, R VUR, L UPJO NA
FREM2g c.4031G>A p.Arg 1344His Het D. rerio 0.085 Del./ 16 0/23/4277 12/102/277164 Uncertain significance DM Progressive renal impairment
B24s ETV4g Recessive c.1244G>A p.Arg 415His Hom Drosphilia melanogaster 1.00 Del. D.C. 36 0/1/4299 0/23/245730 Likely pathogenic Gene R VUR Variant het in unaffected mother, paternal DNA NA
B196 CTU2g Recessive c.1399C>T p.Arg 467Cys Hom D. melanogastert 0.926 Del. D.C. 21 / 0/1/245354 Likely pathogenic Gene L hydronephrosis Variant het in unaffected mother, paternal DNA NA
Facial dysmorphism
Microcephaly
Intellectual disability
Growth retardation
Pulmonary stenosis
Imperforate anus
Absent uterus
B268u HPSE2g Recessive c.457C>T p.Arg 153*i Hom — / 10 / 0/3/245274 Pathogenic DM Urofacial syndrome NA
L RHD, L UPJO
A3837 TBX18g Dominant c.1802A>G p.Gln 601Arg Het Ciona intestinalis 0.932 Del. D.C. 14 / 0/4/217866 Uncertain significance Gene PUV, BL VUR NA
A3900 FRAS1g Compound het c.3998T>C p.Val 1333Ala Het C. elegansv 0.086 Tol. D.C. 15 / 0/12/244984 Uncertain significance Gene PUV NA
FRAS1g c.8131T>C p.Tyr 2711His Het C. elegans 0.928 Del. D.C. 13 / 1/29/191356 Uncertain significance Gene
B211 Trisomy 18g De novo dominant — / / R MCDK, L RHD NA
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
B630 HNF1Bg Dominant 1.5-Mb deletion chromosome 17q12 Pathogenic DM BL MCDK NA
Hyperuricemia ADHD
Developmental delay
B1434 CTU2g Recessive c.1399C>T p.Arg 467Cys Hom D. melanogasterw 0.926 Del. D.C. 21 / 0/1/245354 Likely pathogenic Gene R MCDK, L hydronephrosis NA
Global developmental delay
Brain MRI; cave of septum pellucidium
B1435 ACTG1g De novo c.464C>T p.Ser 155Phe Het S. cerevisiae 1.00 Del. D.C. 18 / / Pathogenic DM L partial duplex kidney, L hydroureter, L hydronephrosis, NA
Facial dysmorphism, lissencephaly, Dany–Walker malformation, global developmental delay
Growth retardation
B1439 SALL1g Dominant c.1666G>A p.Gly 556Ser Het D. rerio 0.999 Del. D.C. 20 / 0/3/245992 Uncertain significance Gene BL VUR, BL hydronephrosis NA
B1316 GREB1Lg Dominant c.4276G>A p.Val 1426Ile Het D. rerioy 0.079 Tol. D.C. 14 / / Likely pathogenic Gene BL RHD NA
Facial dysmorphism
Short neck
Single transverse palmar crease
Brachydactyly
A1261x GREB1Lg Dominant c.5068G>A p.Val1690Met Het X. tropicalis 0.681 Del. D.C. 30 / / Likely pathogenic Gene BL VUR Yes (segregates in multiple affected family members)
L RA
Supernumerary nipple
F1436 KAT6Bg Dominant/de novo c.4285G>A p.Glu1429Lys Het D. rerio 0.995 Tol. D.C. 8 / / Likely pathogenic Gene BL VUR, BL RHD NA
Facial dysmorphism
Microcephaly
Developmental delay
Dysplastic ears
Muscle weakness (pectoralis and trapezius with limited mobility of shoulder)
B1650 HPSE2g Recessive c.1099–2A>G 100% ESS Hom — / NA / / Pathogenic Gene Urofacial syndrome “inverted smile” Yes (unaffected parents het carriers, variant segregates in two affected siblings)
BL VUR
Hinman syndrome
A3962 NPHP1z Recessive c.1804delA p.Ser 602Val fs*4i Hom — / NA / 0/1/245974 Pathogenic Gene BL RHD NA
A4235 TMEM 231z Recessive c.119T>G p.Leu40Arg Hom C. elegans 0.951 Del. D.C. 23 / / Likely pathogenic Gene BL RHD, Facial dysmorphism, microcephaly, intellectual disability, polysyndactyly, heart anomalies, growth retardation. Yes (segregates in two affected family members)
B1306 NPHP4z Compound het c.3983C>T p.Pro1328Leu Het C. elegans 0.999 Del. / 26 0/4/2047 0/62/268266 Likely pathogenic Gene BL RHD NA
NPHP4z c.2021G>A p.Arg674His Het C. elegans 0.999 Del. / 29 0/1/2089 0/8/277216 Likely pathogenic Gene Growth 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; (https://portal.biobaseinternational.com/hgmd). 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.