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CAKUT v1.177 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome, 243605; bilateral renal hypoplasia; Duodenal atresia; Hydronephrosis to Stromme syndrome, OMIM:243605
CAKUT v1.176 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Pallister-Hall syndrome to Pallister-Hall syndrome, OMIM:146510
CAKUT v1.175 ROBO1 Arina Puzriakova Phenotypes for gene: ROBO1 were changed from unilateral kidney agenesis; bilateral kidney agenesis; vesicoureteral junction obstruction; vesicoureteral reflux; posterior urethral valve; genital malformation; increased kidney echogenicity to Neurooculorenal syndrome, OMIM:620305
CAKUT v1.174 ROBO1 Arina Puzriakova Classified gene: ROBO1 as Green List (high evidence)
CAKUT v1.174 ROBO1 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Laura Claus (UMC). Rating Green as there is enough evidence to support the gene-disease association. Included on the R27 Paediatric disorders GMS panel via inclusion on the R29 Intellectual disability panel.

Biallelic variants in the ROBO1 gene are associated with neurooculorenal syndrome (OMIM:620305). Clinical manifestations are generally highly variable and involve several organ systems which may be include a syndromic form of congenital anomalies of the kidney and urinary tract (CAKUT) (PMID: 35227688)
CAKUT v1.174 ROBO1 Arina Puzriakova Gene: robo1 has been classified as Green List (High Evidence).
CAKUT v1.173 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due tocytochrome c oxidase deficiency to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046; Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due tocytochrome c oxidase deficiency
CAKUT v1.172 CHRM3 Arina Puzriakova Classified gene: CHRM3 as Green List (high evidence)
CAKUT v1.172 CHRM3 Arina Puzriakova Added comment: Comment on list classification: Two unrelated families with urinary bladder disease (PMIDs: 22077972; 31441039) have now been published (including the one previously reviewed by Adrian Woolf in 2016), and given that the null mutant mouse model recapitulates the human phenotype (PMID: 10944224), this gene has now been promoted to Green status.
CAKUT v1.172 CHRM3 Arina Puzriakova Gene: chrm3 has been classified as Green List (High Evidence).
CAKUT v1.171 CHRM3 Arina Puzriakova Publications for gene: CHRM3 were set to Weber S, Thiele H, Mir S, Toliat MR, Sozeri B, Reutter H, Draaken M, Ludwig M, Altmüller J, Frommolt P, Stuart HM, Ranjzad P, Hanley NA, Jennings R, Newman WG, Wilcox DT, Thiel U, Schlingmann K-P, Beetz R, Hoyer PF, Konrad M, Schaefer F, Nürnberg P, Woolf AS. Muscarinic acetylcholine receptor M3 mutation causes urinary bladder disease and a prune-belly-like syndrome. Am J Hum Genet 89:668-674, 2011.
CAKUT v1.170 CHRM3 Arina Puzriakova Phenotypes for gene: CHRM3 were changed from Prune Belly-Like Syndrome; Low pressure congenital megabladder to Prune belly syndrome, OMIM:100100; Megacystis; Urinary Bladder Disease
CAKUT v1.169 ZMYM2 Sarah Leigh Phenotypes for gene: ZMYM2 were changed from CAKUT; Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, OMIM:619522
CAKUT v1.168 TMEM260 Eleanor Williams Classified gene: TMEM260 as Green List (high evidence)
CAKUT v1.168 TMEM260 Eleanor Williams Gene: tmem260 has been classified as Green List (High Evidence).
CAKUT v1.167 TMEM260 Eleanor Williams Tag Q4_21_rating was removed from gene: TMEM260.
CAKUT v1.167 TMEM260 Eleanor Williams commented on gene: TMEM260
CAKUT v1.167 ROBO1 Laura Claus gene: ROBO1 was added
gene: ROBO1 was added to CAKUT. Sources: Literature
Mode of inheritance for gene: ROBO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ROBO1 were set to 35227688
Phenotypes for gene: ROBO1 were set to unilateral kidney agenesis; bilateral kidney agenesis; vesicoureteral junction obstruction; vesicoureteral reflux; posterior urethral valve; genital malformation; increased kidney echogenicity
Review for gene: ROBO1 was set to GREEN
Added comment: Sources: Literature
CAKUT v1.167 TRAP1 Eleanor Williams Tag gene-checked tag was added to gene: TRAP1.
CAKUT v1.167 GREB1L Eleanor Williams Tag gene-checked tag was added to gene: GREB1L.
CAKUT v1.167 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
CAKUT v1.167 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
CAKUT v1.166 LIFR Eleanor Williams Added comment: Comment on mode of inheritance: Mode of inheritance of MONOALLELIC is correct for the CAKUT phenotype.
CAKUT v1.166 LIFR Eleanor Williams Mode of inheritance for gene: LIFR was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
CAKUT v1.165 TMEM260 Sarah Leigh edited their review of gene: TMEM260: Changed rating: AMBER
CAKUT v1.165 TMEM260 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least eight variants have been reported in at least six unrelated cases. The variants included: one multi-exon deletion resulting in a frameshift, two smaller frameshifting deletions, two nonsense, one splicing change and two missense changes, one of which was shown by cDNA sequencing to result in skipping of exon 3 (PMID 34612517).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least eight variants have been reported in at least six unrelated cases. The variants included: one multi-exon deletion resulting in a frameshift, two smaller frameshifting deletions, two nonsense, one splicing change and two missense changes, one of which was shown by cDNA sequencing to result in skipping of exon 3 (PMID 34612517). Renal features were seen in patients as follows: elevated creatinine levels (6/12), horse-shoe kidneys (1/12) and renal cysts (1/12)(PMID 34612517).
CAKUT v1.165 TMEM260 Sarah Leigh Deleted their comment
CAKUT v1.165 TMEM260 Sarah Leigh Entity copied from Fetal anomalies v1.749
CAKUT v1.165 TMEM260 Sarah Leigh gene: TMEM260 was added
gene: TMEM260 was added to CAKUT. Sources: Expert Review Amber,PAGE DD-Gene2Phenotype
Q4_21_rating tags were added to gene: TMEM260.
Mode of inheritance for gene: TMEM260 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM260 were set to 28318500; 34612517
Phenotypes for gene: TMEM260 were set to Structural heart defects and renal anomalies syndrome, OMIM:617478; Structural heart defects and renal anomalies syndrome, MONDO:0044321
CAKUT v1.164 DSTYK Zornitza Stark reviewed gene: DSTYK: Rating: RED; Mode of pathogenicity: None; Publications: 23862974; Phenotypes: Congenital anomalies of kidney and urinary tract 1, MIM# 610805; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
CAKUT v1.164 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Alagille syndrome 1 118450 to Alagille syndrome 1, OMIM:118450
CAKUT v1.163 WBP11 Ivone Leong Phenotypes for gene: WBP11 were changed from malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems to Vertebral, cardiac, tracheoesophageal, renal, and limb defects, OMIM:619227
CAKUT v1.162 PLVAP Ivone Leong Classified gene: PLVAP as Green List (high evidence)
CAKUT v1.162 PLVAP Ivone Leong Gene: plvap has been classified as Green List (High Evidence).
CAKUT v1.161 PLVAP Ivone Leong gene: PLVAP was added
gene: PLVAP was added to CAKUT. Sources: Literature
Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLVAP were set to 29875123; 29661969; 26207260; 31215290
Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, OMIM:618183
Review for gene: PLVAP was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. It is currently Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.36) with the following reviews:

"Diarrhoea-10 is a protein-losing enteropathy characterized by intractable secretory diarrhoea and massive protein loss due to leaky fenestrated capillaries. Features include early-onset anasarca, severe hypoalbuminemia, hypogammaglobulinemia, and hypertriglyceridemia, as well as electrolyte abnormalities. Some patients exhibit facial dysmorphism and cardiac and renal anomalies. Intrafamilial variability has been observed, and the disease can be severe, with death occurring in infancy in some patients. Four unrelated families reported. Sources: Expert Review
Zornitza Stark (Australian Genomics), 5 Jan 2021"

"Comment on publications: PMID: 26207260. Patient is of Afgan descent born to consanguineous parents. Presented at 8 days of life with secretory diarrhea, metabolic acidosis, lethargy, poor feeding, and severe hyponatremia causing seizures. Further examination shows patient had bilateral colobomas, undescended testes, mildly dysplastic kidneys bilaterally, low-set ears, and micrognathia. PMID: 29875123. 2 patients (first cousins) from a Muslim Arab consanguineous kindred presented with anasarca, severe hypoalbuminaemia and hypogammaglobinaemia. PMID: 29661969. Patient is of Turkish descent born to consanguineous parents. Presented with severe haematochezia and moderate anasarca. Other findings: dysmorphism, metabolic acidosis, electrolyte deficiencies, elevated GGT, choroid plexus cysts, iris cysts, ASD, VSD, dilated megaureter with dilated renal pelvis, venous thrombosis. PMID: 31215290. Patient born to consanguineous parents. As well as intestinal phenotypes, she also had dysmorphic features, renal and cardiac phenotypes.
Ivone Leong (Genomics England Curator), 12 Apr 2021"

After discussion with the Geomics England Clinical Team it was decided that this gene should also be on this panel.
Sources: Literature
CAKUT v1.160 WBP11 Eleanor Williams Classified gene: WBP11 as Green List (high evidence)
CAKUT v1.160 WBP11 Eleanor Williams Added comment: Comment on list classification: Added to the panel at the suggestion of Genomics England clinicians. Promoting from red to green based on 4 unrelated cases with a renal phenotype.
CAKUT v1.160 WBP11 Eleanor Williams Gene: wbp11 has been classified as Green List (High Evidence).
CAKUT v1.159 WBP11 Eleanor Williams changed review comment from: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies.
Sources: Literature; to: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies.

A renal phenotype was seen in 5/13 patients from 4 families.
Sources: Literature
CAKUT v1.159 WBP11 Eleanor Williams gene: WBP11 was added
gene: WBP11 was added to CAKUT. Sources: Literature
Mode of inheritance for gene: WBP11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WBP11 were set to 33276377
Phenotypes for gene: WBP11 were set to malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems
Review for gene: WBP11 was set to GREEN
Added comment: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies.
Sources: Literature
CAKUT v1.158 MYOCD Arina Puzriakova Phenotypes for gene: MYOCD were changed from Megabladder, congenital 618719 to Megabladder, congenital, OMIM:618719; Megabladder, congenital, MONDO:0032879
CAKUT v1.157 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
CAKUT v1.157 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
CAKUT v1.156 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to CAKUT. Sources: Literature
watchlist tags were added to gene: HS2ST1.
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. This gene has been given an Amber rating.
Sources: Literature
CAKUT v1.155 ZMYM2 Ivone Leong Classified gene: ZMYM2 as Green List (high evidence)
CAKUT v1.155 ZMYM2 Ivone Leong Gene: zmym2 has been classified as Green List (High Evidence).
CAKUT v1.154 ZMYM2 Ivone Leong gene: ZMYM2 was added
gene: ZMYM2 was added to CAKUT. Sources: Expert Review
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to CAKUT; Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly
Review for gene: ZMYM2 was set to GREEN
Added comment: Review by Konstantinos Varvagiannis on the Intellectual disability panel:
"Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features. DD and ID were reported in some of the families described to date as summarized below. You might consider inclusion with green/amber rating in the ID panel and green in the panel for CAKUT.

--

Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants. [Article not reviewed in detail].

Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly.

14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family.

The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT.

ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body).

It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors.

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Literature
Created: 19 Sep 2020, 1:07 a.m."

Based on the expert review and evidence, there is enough evidence to support a gene-disease association. Therefore, this gene has been given a Green rating.
Sources: Expert Review
CAKUT v1.153 FOXC1 Zornitza Stark edited their review of gene: FOXC1: Changed rating: AMBER
CAKUT v1.153 FOXC1 Zornitza Stark reviewed gene: FOXC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32475988; Phenotypes: Congenital anomalies of the kidney and urinary tract (CAKUT); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
CAKUT v1.153 CHD1L Eleanor Williams Classified gene: CHD1L as Red List (low evidence)
CAKUT v1.153 CHD1L Eleanor Williams Added comment: Comment on list classification: Following expert review that some of the reported variants in this gene are relatively common in gnomAD and therefore unlikely to associated with a Mendelian disease, downgrading this gene from amber to red.
CAKUT v1.153 CHD1L Eleanor Williams Gene: chd1l has been classified as Red List (Low Evidence).
CAKUT v1.152 DACT1 Eleanor Williams Tag watchlist tag was added to gene: DACT1.
CAKUT v1.152 FOXD2 Eleanor Williams Tag watchlist tag was added to gene: FOXD2.
CAKUT v1.152 CHD1L Zornitza Stark edited their review of gene: CHD1L: Added comment: Re-evaluation in light of population data: the 6 missense variants reported in the two papers (PMID: 22146311, 24429398) are very common in gnomAD: CHD1L:c.2098G>A; p.Gly700Arg - 1110 hets, 5 hom CHD1L:c.2295A>G; p.Ile765Met - 468 hets, 1 hom CHD1L:c.2479A>G; p.Ile827Val – 725 hets, 2 hom CHD1L:c.998C>G; p.Pro333Arg – 1 het, 0 hom CHD1L:c.1199A>G; p.Glu400Gly – 3 hets, 0 hom CHD1L:c.1551A>G; p.Ile517Met – 195 hets, 0 hom I could not find any other papers for this gene in association with CAKUT. ClinVar only has 1 frameshift variant reported as pathogenic from research in 2001 for an unrelated condition (short stature), the other variants reported in this gene are VUS or LB/B. These population variant frequencies are out of keeping for a Mendelian disorder.; Changed rating: RED; Changed publications: 22146311, 24429398
CAKUT v1.152 DACT1 Eleanor Williams changed review comment from: Conference presentation/abstract - C14.2 - Heterozygous DACT1 mutations in patients with renal anomalies and features of Townes-Brocks syndrome Helge Martens - WES in a patient with renal anomalies, i.e. left-sided agenesis and right-sided duplex, who also had extrarenal abnormalities, e.g. anorectal and sacral malformation, They found a rare heterozygous missense variant in DACT1 gene. The variant was inherited from an unaffected mother. Then looked in further patients and found 7 maternally inherited, heterozygous, likely pathogenic DACT1 missense variants in 8 of 209 families. Appears to be reduced penetrance. Functional assays found Dact1 expression in different organs including anal canal and kidney, whereby renal expression was confined to the mesenchyme of ureter, kidney capsule, cortical and medullary stroma in mouse embryos. CRISPR/Cas9-derived Dact1-deficient murine inner medullary collecting duct cells showed impaired tubule formation. No publication relating to this data is found in PubMed.; to: ESHG 2020 Conference presentation/abstract - C14.2 - Heterozygous DACT1 mutations in patients with renal anomalies and features of Townes-Brocks syndrome Helge Martens - WES in a patient with renal anomalies, i.e. left-sided agenesis and right-sided duplex, who also had extrarenal abnormalities, e.g. anorectal and sacral malformation, They found a rare heterozygous missense variant in DACT1 gene. The variant was inherited from an unaffected mother. Then looked in further patients and found 7 maternally inherited, heterozygous, likely pathogenic DACT1 missense variants in 8 of 209 families. Appears to be reduced penetrance. Functional assays found Dact1 expression in different organs including anal canal and kidney, whereby renal expression was confined to the mesenchyme of ureter, kidney capsule, cortical and medullary stroma in mouse embryos. CRISPR/Cas9-derived Dact1-deficient murine inner medullary collecting duct cells showed impaired tubule formation. No publication relating to this data is found in PubMed.
CAKUT v1.152 DACT1 Eleanor Williams commented on gene: DACT1
CAKUT v1.152 FOXD2 Eleanor Williams gene: FOXD2 was added
gene: FOXD2 was added to CAKUT. Sources: Other
Mode of inheritance for gene: FOXD2 was set to BIALLELIC, autosomal or pseudoautosomal
Added comment: Conference presentation/abstract ESGH 2020 - Implication of FOXD2 in autosomal recessive syndromic CAKUT Korbinian M. Riedhammer Report index patient with CAKUT with a homozygous frameshift variant in FOXD2 NM_004474.3:c.789dup, p.(Gly264Argfs*228). The patient presented with bilateral hypoplastic kidneys, facial dysmorphism, developmental delay. Another affected family member was found to have the same variant. FOXD2 is a transcription factor with strong expression in the developing kidney. Foxd2-/- mice can show a CAKUT phenotype. No publications in PubMed relating to this data are currently found.
Sources: Other
CAKUT v1.151 BMP4 Rebecca Foulger changed review comment from: Kept rating as Amber following agreement from Helen Brittain, Genomics England Clinical Team: evidence is borderline and. further cases or supportive evidence is needed to be confident of a causal link. Rated Amber but can be re-assessed by GLH groups at a future date.; to: Kept rating as Amber following agreement from Helen Brittain, Genomics England Clinical Team: evidence is borderline and further cases or supportive evidence is needed to be confident of a causal link. Rated Amber but can be re-assessed by GLH groups at a future date.
CAKUT v1.151 RPGRIP1L Sarah Leigh changed review comment from: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RPGRIP1L variants are ciliopathies. It is green on Renal ciliopathies (https://panelapp.genomicsengland.co.uk/panels/725/gene/RPGRIP1L/) and Rare multisystem ciliopathy disorders (https://panelapp.genomicsengland.co.uk/panels/150/gene/RPGRIP1L/) panels.; to: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RPGRIP1L variants are ciliopathies and therefore not appropriate for the CAKUT panel. It is green on Renal ciliopathies (https://panelapp.genomicsengland.co.uk/panels/725/gene/RPGRIP1L/) and Rare multisystem ciliopathy disorders (https://panelapp.genomicsengland.co.uk/panels/150/gene/RPGRIP1L/) panels.
CAKUT v1.151 RRM2B Sarah Leigh Classified gene: RRM2B as Red List (low evidence)
CAKUT v1.151 RRM2B Sarah Leigh Added comment: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RRM2B variants are metabolic renal disease / renal tubulopathy. RRM2B is green on Mitochondrial disorders (https://panelapp.genomicsengland.co.uk/panels/112/gene/RRM2B/) and Inborn errors of metabolism (https://panelapp.genomicsengland.co.uk/panels/467/gene/RRM2B/) panels.
CAKUT v1.151 RRM2B Sarah Leigh Gene: rrm2b has been classified as Red List (Low Evidence).
CAKUT v1.150 NIPBL Sarah Leigh Publications for gene: NIPBL were set to 8291537; 16799922; 15146186; 15146185; 15318302
CAKUT v1.149 NIPBL Sarah Leigh Classified gene: NIPBL as Green List (high evidence)
CAKUT v1.149 NIPBL Sarah Leigh Gene: nipbl has been classified as Green List (High Evidence).
CAKUT v1.148 NIPBL Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 13 variants reported, however, there seems to be little evidence of renal involvement.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 13 variants reported. PMID 8291540 presents extensive evidence for renal involvement in 61 Cornelia de Lange syndrome 1 cases; including structural anomalies of the kidney system in 25 (41%): absent or poor corticomedullary differentiation (8 cases), pelvic dilation (6 cases), vesicoureteral reflux (5 cases), small kidney (3 cases), isolated renal cyst (3 cases), renal ectopia (2 cases), renal function reduced (9 cases).
CAKUT v1.148 RPGRIP1L Sarah Leigh Classified gene: RPGRIP1L as Red List (low evidence)
CAKUT v1.148 RPGRIP1L Sarah Leigh Added comment: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RPGRIP1L variants are ciliopathies. It is green on Renal ciliopathies (https://panelapp.genomicsengland.co.uk/panels/725/gene/RPGRIP1L/) and Rare multisystem ciliopathy disorders (https://panelapp.genomicsengland.co.uk/panels/150/gene/RPGRIP1L/) panels.
CAKUT v1.148 RPGRIP1L Sarah Leigh Gene: rpgrip1l has been classified as Red List (Low Evidence).
CAKUT v1.147 ROR2 Sarah Leigh Added comment: Comment on mode of inheritance: Based on Gen2Phen confirmed rating of disease association including hydronephrosis in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
CAKUT v1.147 ROR2 Sarah Leigh Mode of inheritance for gene: ROR2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
CAKUT v1.146 ROR2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene, where hydronephrosis is reported in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
At least 8 variants reported have been reported in Robinow syndrome recessive in the literature (PMID 10932187;19640924;18831060), however, renal anomolies were only reported in one case (PMID 15952209).; to: Comment on list classification: Associated with relevant phenotype in OMIM and as Confirmed Gen2Phen gene, where hydronephrosis is reported in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
At least 8 variants reported have been reported in Robinow syndrome, autosomal recessive 268310 in the literature (PMID 10932187;19640924;18831060), however, renal anomolies were only reported in one case (PMID 15952209).

Green rating is based on Expert review by Zornitza Stark that ~10% of cases of Robinow syndrome, autosomal recessive 268310 have renal abnormalities and because of the Confirmed Gen2Phen rating.
CAKUT v1.146 ROR2 Sarah Leigh Classified gene: ROR2 as Green List (high evidence)
CAKUT v1.146 ROR2 Sarah Leigh Gene: ror2 has been classified as Green List (High Evidence).
CAKUT v1.145 ROR2 Sarah Leigh Classified gene: ROR2 as Amber List (moderate evidence)
CAKUT v1.145 ROR2 Sarah Leigh Gene: ror2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.144 ROR2 Sarah Leigh Classified gene: ROR2 as Green List (high evidence)
CAKUT v1.144 ROR2 Sarah Leigh Gene: ror2 has been classified as Green List (High Evidence).
CAKUT v1.143 ROR2 Sarah Leigh Classified gene: ROR2 as Amber List (moderate evidence)
CAKUT v1.143 ROR2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene, where hydronephrosis is reported in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
At least 8 variants reported have been reported in Robinow syndrome recessive in the literature (PMID 10932187;19640924;18831060), however, renal anomolies were only reported in one case (PMID 15952209).
CAKUT v1.143 ROR2 Sarah Leigh Gene: ror2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.142 ROR2 Sarah Leigh Publications for gene: ROR2 were set to
CAKUT v1.141 ROR2 Sarah Leigh Phenotypes for gene: ROR2 were changed from Robinow syndrome, autosomal recessive, MIM# 268310 to Robinow syndrome, autosomal recessive 268310
CAKUT v1.140 ROBO2 Sarah Leigh Classified gene: ROBO2 as Green List (high evidence)
CAKUT v1.140 ROBO2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 4 families, together with supportive mouse models.
CAKUT v1.140 ROBO2 Sarah Leigh Gene: robo2 has been classified as Green List (High Evidence).
CAKUT v1.139 ROBO2 Sarah Leigh Phenotypes for gene: ROBO2 were changed from Vesicoureteral reflux 2, 610878; Vesicoureteral Reflux to Vesicoureteral reflux 2 610878
CAKUT v1.138 WNT5A Catherine Snow Classified gene: WNT5A as Amber List (moderate evidence)
CAKUT v1.138 WNT5A Catherine Snow Added comment: Comment on list classification: WNT5A associated with Robinow syndrome. Although renal disorder is associated with syndrome limited known variants reported in literature. Lots of functional models in mice therefore rating as Amber due to lack of human variants
CAKUT v1.138 WNT5A Catherine Snow Gene: wnt5a has been classified as Amber List (Moderate Evidence).
CAKUT v1.137 WNT5A Catherine Snow Publications for gene: WNT5A were set to 27002738; 31032853
CAKUT v1.137 WNT5A Catherine Snow Publications for gene: WNT5A were set to 27002738
CAKUT v1.136 WNT5A Catherine Snow Publications for gene: WNT5A were set to
CAKUT v1.135 ROBO2 Sarah Leigh Publications for gene: ROBO2 were set to
CAKUT v1.134 NIPBL Sarah Leigh Classified gene: NIPBL as Amber List (moderate evidence)
CAKUT v1.134 NIPBL Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 13 variants reported, however, there seems to be little evidence of renal involvement.
CAKUT v1.134 NIPBL Sarah Leigh Gene: nipbl has been classified as Amber List (Moderate Evidence).
CAKUT v1.133 TBC1D1 Catherine Snow Classified gene: TBC1D1 as Green List (high evidence)
CAKUT v1.133 TBC1D1 Catherine Snow Added comment: Comment on list classification: Functional work in mouse and one paper with four unrelated individuals with pedigree analysis show evidence for a role of TBC1D1 variants in CAKUT pathogenesis. Although only identified in PMID: 26572137 paper sufficient evidence to rate TBC1D1 as Green
CAKUT v1.133 TBC1D1 Catherine Snow Gene: tbc1d1 has been classified as Green List (High Evidence).
CAKUT v1.132 NIPBL Sarah Leigh Publications for gene: NIPBL were set to 8291537; 16799922; 15146186; 15146185; 15318302
CAKUT v1.131 NIPBL Sarah Leigh Phenotypes for gene: NIPBL were changed from Cornelia de Lange syndrome 1, MIM# 122470 to Cornelia de Lange syndrome 1 122470
CAKUT v1.130 NIPBL Sarah Leigh Publications for gene: NIPBL were set to 8291537
CAKUT v1.129 VPS33B Catherine Snow Classified gene: VPS33B as Red List (low evidence)
CAKUT v1.129 VPS33B Catherine Snow Added comment: Comment on list classification: Downgraded following identification by expert review as VPS33B is a tubulopathy gene.
CAKUT v1.129 VPS33B Catherine Snow Gene: vps33b has been classified as Red List (Low Evidence).
CAKUT v1.128 STRA6 Catherine Snow Classified gene: STRA6 as Green List (high evidence)
CAKUT v1.128 STRA6 Catherine Snow Added comment: Comment on list classification: Sufficient number of unrelated cases identified in the literature to classify STRA6 Green for this panel
CAKUT v1.128 STRA6 Catherine Snow Gene: stra6 has been classified as Green List (High Evidence).
CAKUT v1.127 STRA6 Catherine Snow Publications for gene: STRA6 were set to 26373900; 17503335
CAKUT v1.127 STRA6 Catherine Snow Publications for gene: STRA6 were set to
CAKUT v1.126 SLIT2 Catherine Snow Classified gene: SLIT2 as Amber List (moderate evidence)
CAKUT v1.126 SLIT2 Catherine Snow Added comment: Comment on list classification: Gene identified as missing from panel by expert reviewer. Rating as Amber as gene disease only reported in PMID:26026792 no further evidence of this association and missing segregation information for some of the three individuals.
CAKUT v1.126 SLIT2 Catherine Snow Gene: slit2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.125 SLIT2 Catherine Snow Publications for gene: SLIT2 were set to
CAKUT v1.124 NADSYN1 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families, together with supportive functional studies (PMID 31883644).
CAKUT v1.124 NADSYN1 Sarah Leigh Phenotypes for gene: NADSYN1 were changed from Multiple congenital abnormalities; absent kidneys; cardiac; limb; vertebral to Vertebral, cardiac, renal, and limb defects syndrome 3 618845
CAKUT v1.123 NADSYN1 Sarah Leigh Classified gene: NADSYN1 as Green List (high evidence)
CAKUT v1.123 NADSYN1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families.
CAKUT v1.123 NADSYN1 Sarah Leigh Gene: nadsyn1 has been classified as Green List (High Evidence).
CAKUT v1.122 SALL4 Catherine Snow Classified gene: SALL4 as Amber List (moderate evidence)
CAKUT v1.122 SALL4 Catherine Snow Added comment: Comment on list classification: This gene has evidence of a gene phenotype relationship from one active group however since 2006 no further gene disease relationship has been reported. SALL4 recently associated with leukemic hematopoiesis. Therefore due to lack of recent association rating gene as Amber
CAKUT v1.122 SALL4 Catherine Snow Gene: sall4 has been classified as Amber List (Moderate Evidence).
CAKUT v1.121 SALL4 Catherine Snow Phenotypes for gene: SALL4 were changed from SALL4- related disorders to Duane-radial ray syndrome, 607323
CAKUT v1.120 MYOCD Sarah Leigh Classified gene: MYOCD as Green List (high evidence)
CAKUT v1.120 MYOCD Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 4 variants reported in at least 4 unrelated cases, together with a supportive loss of function mouse model. PMID 31513549 concludes "that monoallelic loss-of-function variants in MYOCD cause congenital megabladder in males and that biallelic variants are associated with disease manifest in females that also involves the cardiovascular system".
CAKUT v1.120 MYOCD Sarah Leigh Gene: myocd has been classified as Green List (High Evidence).
CAKUT v1.119 MYOCD Sarah Leigh Phenotypes for gene: MYOCD were changed from Megabladder; congenital heart disease; cardiomyopathy to Megabladder, congenital 618719
CAKUT v1.118 MYOCD Sarah Leigh Publications for gene: MYOCD were set to PMID: 31513549
CAKUT v1.117 NOTCH2 Sarah Leigh Classified gene: NOTCH2 as Green List (high evidence)
CAKUT v1.117 NOTCH2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 10 variants reported been reported in unrealated with features of Alagille syndrome (PMID 22209762).
CAKUT v1.117 NOTCH2 Sarah Leigh Gene: notch2 has been classified as Green List (High Evidence).
CAKUT v1.116 NOTCH2 Sarah Leigh Publications for gene: NOTCH2 were set to 22105858; 16773578
CAKUT v1.115 NOTCH2 Sarah Leigh Publications for gene: NOTCH2 were set to 22105858
CAKUT v1.114 NOTCH2 Sarah Leigh Publications for gene: NOTCH2 were set to PMID: 22105858
CAKUT v1.113 NOTCH2 Sarah Leigh Added comment: Comment on phenotypes: Alagille syndrome 2 610205
CAKUT v1.113 NOTCH2 Sarah Leigh Phenotypes for gene: NOTCH2 were changed from Alagille syndrome 2; OMIM #610205 to Alagille syndrome 2 610205
CAKUT v1.112 DHCR7 Rebecca Foulger Classified gene: DHCR7 as Green List (high evidence)
CAKUT v1.112 DHCR7 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green on advice from Helen Brittain (Genomics England Clinical Team). Helen notes that it meets the inclusion criteria (renal malformations as part of a wider syndromic phenotype). There are other post-natally relevant renal malformations (unilateral agenesis, hydronephrosis and cysts). It is also a gene that we have a biochemical test for, so VUSs would be easier to re-categorise than some genes.
CAKUT v1.112 DHCR7 Rebecca Foulger Gene: dhcr7 has been classified as Green List (High Evidence).
CAKUT v1.111 EXOC3L2 Rebecca Foulger Tag watchlist tag was added to gene: EXOC3L2.
CAKUT v1.111 EXOC3L2 Rebecca Foulger Classified gene: EXOC3L2 as Amber List (moderate evidence)
CAKUT v1.111 EXOC3L2 Rebecca Foulger Added comment: Comment on list classification: Agreed by Helen Brittain (Genomics England clinical team) that Amber rating is appropriate here: only one case that didn't lead to fetal demise. Added 'watchlist' tag awaiting further cases.
CAKUT v1.111 EXOC3L2 Rebecca Foulger Gene: exoc3l2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.110 TBX18 Rebecca Foulger Phenotypes for gene: TBX18 were changed from to CAKUT; Renal cysts and diabetes; glomerulocystic kidney disease; hypomagneseamia; Congenital anomalies of kidney and urinary tract 2, 143400
CAKUT v1.109 TBX18 Rebecca Foulger Publications for gene: TBX18 were set to
CAKUT v1.108 LRIG2 Rebecca Foulger Publications for gene: LRIG2 were set to Stuart HM, Roberts NA, Bergu B, Daly SB, Urquhart JE, Bhaskar S, Dickerson J, Mermerkaya M, Silay MS, Lewis MA, Olondriz BO, Gener B, Beetz C, Varga RE, Gülpınar O, Süer E, Yalçınkaya F, Gücük A, Yue WW, Erdogan F, Berry A, Hanley NA, McKenzie EA, Hilton EN, Woolf AS, Newman WG. LRIG2 mutations cause urofacial syndrome. Am J Hum Genet 92:259-264, 2013.
CAKUT v1.107 ACE Rebecca Foulger Publications for gene: ACE were set to
CAKUT v1.106 GPC3 Ivone Leong Classified gene: GPC3 as Green List (high evidence)
CAKUT v1.106 GPC3 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. Based on the review and literature there is enough evidence to support a gene-disease association. Therefore, this gene has been given Green status.
CAKUT v1.106 GPC3 Ivone Leong Gene: gpc3 has been classified as Green List (High Evidence).
CAKUT v1.105 GPC3 Ivone Leong Publications for gene: GPC3 were set to
CAKUT v1.104 HOXA13 Ivone Leong Classified gene: HOXA13 as Green List (high evidence)
CAKUT v1.104 HOXA13 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. Based on the review and available literature there is enough evidence to support a gene-disease association. Therefore, this gene has been given a Green status.
CAKUT v1.104 HOXA13 Ivone Leong Gene: hoxa13 has been classified as Green List (High Evidence).
CAKUT v1.103 HOXA13 Ivone Leong Publications for gene: HOXA13 were set to
CAKUT v1.102 LIFR Ivone Leong Classified gene: LIFR as Green List (high evidence)
CAKUT v1.102 LIFR Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. Based on the review and the evidence there is enough evidence to support a gene-disease association. Therefore, this gene has been given Green status.
CAKUT v1.102 LIFR Ivone Leong Gene: lifr has been classified as Green List (High Evidence).
CAKUT v1.101 LRP4 Ivone Leong Classified gene: LRP4 as Green List (high evidence)
CAKUT v1.101 LRP4 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. LRP4 is associated with a relevant phenotype in OMIM and Gene2Phenotype, with Gene2Phenotype listing renal agenesis and renal hypoplasia as a phenotype. There are >3 unrelated cases of patients with LRP4 variants who have renal hypoplasia or renal agenesis as a feature. There is also a mouse model. Therefore there is enough evidence to support a gene-disease association for this gene to be Green.
CAKUT v1.101 LRP4 Ivone Leong Gene: lrp4 has been classified as Green List (High Evidence).
CAKUT v1.100 LRP4 Ivone Leong Publications for gene: LRP4 were set to
CAKUT v1.99 LRP4 Ivone Leong Phenotypes for gene: LRP4 were changed from Cenani-Lenz syndactyly syndrome, MIM# 212780 to Cenani-Lenz syndactyly syndrome, 212780
CAKUT v1.98 LIFR Ivone Leong Publications for gene: LIFR were set to PMID: 28334964
CAKUT v1.97 KMT2D Ivone Leong Classified gene: KMT2D as Green List (high evidence)
CAKUT v1.97 KMT2D Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the evidence and review there is enough evidence to support a gene-disease association; therefore, this gene has been given Green status.
CAKUT v1.97 KMT2D Ivone Leong Gene: kmt2d has been classified as Green List (High Evidence).
CAKUT v1.96 KMT2D Ivone Leong Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, MIM# 147920 to Kabuki syndrome 1, 147920
CAKUT v1.95 KDM6A Ivone Leong Classified gene: KDM6A as Green List (high evidence)
CAKUT v1.95 KDM6A Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the evidence and review there is enough evidence to support a gene-disease association; therefore, this gene has been given Green status.
CAKUT v1.95 KDM6A Ivone Leong Gene: kdm6a has been classified as Green List (High Evidence).
CAKUT v1.94 KDM6A Ivone Leong Mode of inheritance for gene: KDM6A was changed from Other to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
CAKUT v1.93 KDM6A Ivone Leong Phenotypes for gene: KDM6A were changed from Kabuki syndrome 2, MIM# 300867 to Kabuki syndrome 2, 300867
CAKUT v1.92 JAG1 Ivone Leong Classified gene: JAG1 as Green List (high evidence)
CAKUT v1.92 JAG1 Ivone Leong Gene: jag1 has been classified as Green List (High Evidence).
CAKUT v1.91 JAG1 Ivone Leong Classified gene: JAG1 as No list
CAKUT v1.91 JAG1 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer (Chirag Patel (Genetic Health Queensland)). JAG1 is associated with a relevant disease in OMIM and Gene2Phenotype.

Renal structural involvement for cases of Alagille syndrome caused by variants in the JAG1 gene is well known. Based on the expert review and literature evidence there is enough evidence to support a gene-disease assocation. Therefore this gene has been given Green status.
CAKUT v1.91 JAG1 Ivone Leong Gene: jag1 has been removed from the panel.
CAKUT v1.90 JAG1 Ivone Leong Publications for gene: JAG1 were set to 22105858
CAKUT v1.89 JAG1 Ivone Leong Phenotypes for gene: JAG1 were changed from Alagille syndrome 1; OMIM #118450 to Alagille syndrome 1 118450
CAKUT v1.88 JAG1 Ivone Leong Publications for gene: JAG1 were set to PMID: 22105858
CAKUT v1.87 HOXA13 Ivone Leong Phenotypes for gene: HOXA13 were changed from Hand-foot-uterus syndrome, MIM# 140000 to Hand-foot-uterus syndrome, 140000
CAKUT v1.86 GREB1L Ivone Leong Classified gene: GREB1L as Green List (high evidence)
CAKUT v1.86 GREB1L Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. GREB1L is associated with a relevant phenotype in OMIM (there are >3 cases described there). Based on the expert reviews and literature there is enough to support gene-disease association, therefore this gene has been given a Green status.
CAKUT v1.86 GREB1L Ivone Leong Gene: greb1l has been classified as Green List (High Evidence).
CAKUT v1.85 GREB1L Ivone Leong Phenotypes for gene: GREB1L were changed from Renal hypodysplasia/aplasia 3, MIM# 617805 to Renal hypodysplasia/aplasia 3, 617805
CAKUT v1.84 GREB1L Ivone Leong Publications for gene: GREB1L were set to 29100091
CAKUT v1.83 FGF20 Rebecca Foulger Classified gene: FGF20 as Amber List (moderate evidence)
CAKUT v1.83 FGF20 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Amber by Zornitza. One consanguineous family plus functional data from mice studies. Therefore updated rating to Amber.
CAKUT v1.83 FGF20 Rebecca Foulger Gene: fgf20 has been classified as Amber List (Moderate Evidence).
CAKUT v1.82 FGF20 Rebecca Foulger Publications for gene: FGF20 were set to 22698282
CAKUT v1.81 FGF20 Rebecca Foulger commented on gene: FGF20: Functional experiments (in mice) confirm role of FGF20 in kidney development (e.g. PMID:23112089).
CAKUT v1.81 FGF20 Rebecca Foulger Phenotypes for gene: FGF20 were changed from Renal hypodysplasia/aplasia 2, MIM#615721 to ?Renal hypodysplasia/aplasia 2, 615721
CAKUT v1.80 FGF20 Rebecca Foulger changed review comment from: PMID:22698282. Barak et al., 2012 identify a homozygous frameshift truncating variant (c.337delG) in FGF20, which segregated with the disorder in a consanguineous familly. Pregnancies showed anhydramnios and the fetuses had bilateral renal agenesis. All pregnancies were terminated. Mouse model shows loss of Fgf20 resulted in kidney agenesis.; to: PMID:22698282. Barak et al., 2012 identify a consanguineous family where multiple pregnancies showed anhydramnios and the fetuses had bilateral renal agenesis. DNA analysis from the initial fetus identified homozygous variants in four genes expressed during early kidney development. One of these mutations was a single base-pair deletion in exon 2 of FGF20 which segregated with the disorder within the family. All pregnancies were terminated. A mouse model shows loss of Fgf20 resulted in kidney agenesis.
CAKUT v1.80 FGF20 Rebecca Foulger commented on gene: FGF20
CAKUT v1.80 FAM58A Rebecca Foulger Classified gene: FAM58A as Green List (high evidence)
CAKUT v1.80 FAM58A Rebecca Foulger Added comment: Comment on list classification: FAM58A added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Green following literature review: sufficient cases to support gene:disease association, and renal phenotypes are common.
CAKUT v1.80 FAM58A Rebecca Foulger Gene: fam58a has been classified as Green List (High Evidence).
CAKUT v1.79 FAM58A Rebecca Foulger Phenotypes for gene: FAM58A were changed from STAR syndrome, MIM# 300707 to STAR syndrome, 300707; Syndactyly, Telecanthus, Anogenital malformations and Renal malformations
CAKUT v1.78 FAM58A Rebecca Foulger Added comment: Comment on mode of inheritance: Set MOI to XLD to match literature (PMID:28225384, PMID:18297069).
CAKUT v1.78 FAM58A Rebecca Foulger Mode of inheritance for gene: FAM58A was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
CAKUT v1.77 FAM58A Rebecca Foulger Mode of inheritance for gene: FAM58A was changed from Other to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
CAKUT v1.76 FAM58A Rebecca Foulger commented on gene: FAM58A: PMID:28225384 (Lefroy et al., 2017) report a 19 year old woman with STAR syndrome; phenotypes include a small left kidney and impaired renal function. The patient had a Xq28 deletion which included the whole FAM58A gene. The mother was mosaic for the deletion, and had a milder phenotype with normal renal ultrasound and renal function.
CAKUT v1.76 FAM58A Rebecca Foulger commented on gene: FAM58A
CAKUT v1.76 EXOC3L2 Rebecca Foulger Classified gene: EXOC3L2 as Amber List (moderate evidence)
CAKUT v1.76 EXOC3L2 Rebecca Foulger Gene: exoc3l2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.75 EXOC3L2 Rebecca Foulger Classified gene: EXOC3L2 as No list
CAKUT v1.75 EXOC3L2 Rebecca Foulger Added comment: Comment on list classification: Gene was added to panel and rated Green by Chirag Patel. Updated rating from Grey to Amber. Most reported cases are from fetuses (e.g. PMID: 27894351) and therefore EXOC3L2 is more appropriate on Fetal panel.
CAKUT v1.75 EXOC3L2 Rebecca Foulger Gene: exoc3l2 has been removed from the panel.
CAKUT v1.74 EXOC3L2 Rebecca Foulger commented on gene: EXOC3L2: PMID: 27894351: Shaheen et al., 2016 examined 371 individuals from 265 families with ciliopathy phenotypes. They identified a LOF variant in EXOC3L2 and a lethal phenotype that resembles Meckel–Gruber syndrome (severe posterior fossa malformation with kidney enlargement) in one family.
CAKUT v1.74 EXOC3L2 Rebecca Foulger commented on gene: EXOC3L2: PMID: 28749478: Shamseldin et al., 2018 performed exome sequencing as part of molecular autopsy in a cohort of 44 families with at least one death or lethal fetal malformation. They report one fetus with a biallelic EXOC3L2 variant and a phenotype similar to Meckel-Gruber syndrome.
CAKUT v1.74 EXOC3L2 Rebecca Foulger commented on gene: EXOC3L2
CAKUT v1.74 EXOC3L2 Rebecca Foulger Publications for gene: EXOC3L2 were set to PMID: 30327448, 28749478, 27894351
CAKUT v1.73 DHCR7 Rebecca Foulger changed review comment from: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Amber. Renal phenotypes are only seen in approximately 25% of SLOS patients, and renal anomalies are more commonly detected prenatally than postnatally (PMID:23059950) so DHCR7 is more suited to the Fetal anomalies panel.; to: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Amber. Renal phenotypes are only seen in approximately 25% of SLOS patients, and renal anomalies are more commonly detected prenatally than postnatally (PMID:23059950) so DHCR7 is more appropriate for the Fetal anomalies panel.
CAKUT v1.73 DHCR7 Rebecca Foulger changed review comment from: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Amber. Renal phenotypes are only seen in approximately 25% of SLOS patients, and renal anomalies are more commonly detected prenatally than postnatally (PMID:23059950).; to: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Amber. Renal phenotypes are only seen in approximately 25% of SLOS patients, and renal anomalies are more commonly detected prenatally than postnatally (PMID:23059950) so DHCR7 is more suited to the Fetal anomalies panel.
CAKUT v1.73 DHCR7 Rebecca Foulger Classified gene: DHCR7 as Amber List (moderate evidence)
CAKUT v1.73 DHCR7 Rebecca Foulger Gene: dhcr7 has been classified as Amber List (Moderate Evidence).
CAKUT v1.72 DHCR7 Rebecca Foulger Classified gene: DHCR7 as No list
CAKUT v1.72 DHCR7 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Amber. Renal phenotypes are only seen in approximately 25% of SLOS patients, and renal anomalies are more commonly detected prenatally than postnatally (PMID:23059950).
CAKUT v1.72 DHCR7 Rebecca Foulger Gene: dhcr7 has been removed from the panel.
CAKUT v1.71 DHCR7 Rebecca Foulger commented on gene: DHCR7: PMID:9678700. Ryan et al., 1998 reviewed all known UK cases of SLOS. Half had been terminated or died in infancy. 14 (29%) had structural renal abnormalities.
CAKUT v1.71 DHCR7 Rebecca Foulger commented on gene: DHCR7: PMID:23059950. Nowaczyk and Irons, 2012 note that approximately 25% of affected individuals have renal anomalies (most common being renal hypoplasia or agenesis, renal cortical cysts, hydronephrosis and structural anomalies of the collecting system). They also note that renal anomalies are amongst the phenotypes seen more commonly prenatally than postnatally.
CAKUT v1.71 DHCR7 Rebecca Foulger commented on gene: DHCR7: PMID:10069707. Kratz and Kelley, 1999 report on prenatal diagnosis of SLOS. Fetal phenotypes included renal agenesis, renal pyelectasis, hydronephrosis (4 patients)
CAKUT v1.71 DHCR7 Rebecca Foulger Phenotypes for gene: DHCR7 were changed from Smith-Lemli-Opitz syndrome, MIM# 270400 to Smith-Lemli-Opitz syndrome, 270400; renal agenesis
CAKUT v1.70 DHCR7 Rebecca Foulger Publications for gene: DHCR7 were set to 3812577; 10069707; 23059950; 9678700
CAKUT v1.69 DHCR7 Rebecca Foulger commented on gene: DHCR7
CAKUT v1.69 CTU2 Rebecca Foulger Classified gene: CTU2 as Green List (high evidence)
CAKUT v1.69 CTU2 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Zornitza Stark. The Saudi cases all share a founder variant (PMIDs:26633546, 27480277) but a more recent study by the same authors (PMID:31301155) identifies a further 4 patients with a renal phenotype as part of DREAM‐PL syndrome, and new homozygous CTU2 variants. Therefore relevant renal phenotype and sufficient unrelated cases to support association.
CAKUT v1.69 CTU2 Rebecca Foulger Gene: ctu2 has been classified as Green List (High Evidence).
CAKUT v1.68 CTU2 Rebecca Foulger Phenotypes for gene: CTU2 were changed from Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, MIM#618142 to DREAM‐PL syndrome; Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, 618142
CAKUT v1.67 CTU2 Rebecca Foulger commented on gene: CTU2: PMID:31301155 (Shaheen et al., 2019) show that biallelic CTU2 variants cause DREAM-PL syndrome (dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly) in a further 5 patients. 4/5 patients had a renal phenotype. These 5 patients had different variants to the previously described founder variant, including Ala403Cysfs*23, Leu63Pro, p.Ile505Argfs*41.
CAKUT v1.67 CTU2 Rebecca Foulger commented on gene: CTU2: PMID:27480277 (Shaheen et al., 2016) identified 2 male cousins from the United Arab Emirates with the same founder T247T variant. This founder variant has a frequency of 1/769 in Saudi Arabia.
CAKUT v1.67 CTU2 Rebecca Foulger commented on gene: CTU2
CAKUT v1.67 CHRNA3 Rebecca Foulger Classified gene: CHRNA3 as Green List (high evidence)
CAKUT v1.67 CHRNA3 Rebecca Foulger Gene: chrna3 has been classified as Green List (High Evidence).
CAKUT v1.66 CHRNA3 Rebecca Foulger Classified gene: CHRNA3 as No list
CAKUT v1.66 CHRNA3 Rebecca Foulger Added comment: Comment on list classification: Gene was added to panel and rated Green by Zornitza Stark. Sufficient cases (3 unrelated families) from one paper, plus functional studies to support causation and therefore increased rating to Green.
CAKUT v1.66 CHRNA3 Rebecca Foulger Gene: chrna3 has been removed from the panel.
CAKUT v1.65 CHRNA3 Rebecca Foulger commented on gene: CHRNA3
CAKUT v1.65 CHD1L Rebecca Foulger Tag missense tag was added to gene: CHD1L.
CAKUT v1.65 CHD1L Rebecca Foulger Classified gene: CHD1L as Amber List (moderate evidence)
CAKUT v1.65 CHD1L Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber. Although there are 8 families with CAKUT and CHD1L variants, all variants are missense, and there is limited family data available for the patients in PMID:22146311. Also in PMID:22146311, only 2/3 variants were absent from controls, Patient 2 variant was inherited from an asymptomatic mother, and the variant in Patient 3 is predicted benign.
CAKUT v1.65 CHD1L Rebecca Foulger Gene: chd1l has been classified as Amber List (Moderate Evidence).
CAKUT v1.64 CHD1L Rebecca Foulger commented on gene: CHD1L: PMID:32164334 show CNVs in genes including CHD1L in 6 CAKUT patients. One patient with bilateral renal cortical cysts and renal stones (ID 41) had a duplication of 1q21.1 encompassing CHD1L.
CAKUT v1.64 CHD1L Rebecca Foulger Publications for gene: CHD1L were set to 24429398; 22146311
CAKUT v1.63 CHD1L Rebecca Foulger changed review comment from: PMID:24429398 detected heterozygous variants in CHD1L in 5 families with CAKUT (p.P333R in 1 family, p.E400G in 1 family, p.I517M in 3 Indian families).; to: PMID:24429398 (2014) detected heterozygous variants in CHD1L in 5 families with CAKUT (p.P333R in 1 family, p.E400G in 1 family, p.I517M in 3 Indian families).
CAKUT v1.63 CHD1L Rebecca Foulger commented on gene: CHD1L: PMID:24429398 detected heterozygous variants in CHD1L in 5 families with CAKUT (p.P333R in 1 family, p.E400G in 1 family, p.I517M in 3 Indian families).
CAKUT v1.63 CHD1L Rebecca Foulger commented on gene: CHD1L
CAKUT v1.63 TFAP2A Catherine Snow Publications for gene: TFAP2A were set to 21204207; 31160420
CAKUT v1.62 TFAP2A Catherine Snow Publications for gene: TFAP2A were set to 21204207; 31160420
CAKUT v1.62 TFAP2A Catherine Snow Publications for gene: TFAP2A were set to
CAKUT v1.61 TFAP2A Catherine Snow Classified gene: TFAP2A as Green List (high evidence)
CAKUT v1.61 TFAP2A Catherine Snow Added comment: Comment on list classification: TFAP2A identified by expert review. Phenotype for the gene disease association is mainly branchial cleft sinus defects, ocular anomalies such as microphthalmia and lacrimal duct obstruction and a dysmorphic facial appearance including cleft or pseudocleft lip/palate. However PMID: 21204207 - Genotype-phenotype Analysis of the Branchio-Oculo-Facial Syndrome states that renal anomalies, including dysplasia, agenesis,multicystic kidneys, and vesicoureteral reflux was seen in 12/34; 35% who had variants mainly in exon 4 &5 of the TFAP2A gene. Functional evidence PMID: 31160420 demonstrates that TFAP2A is involved in kidney development
CAKUT v1.61 TFAP2A Catherine Snow Gene: tfap2a has been classified as Green List (High Evidence).
CAKUT v1.60 ZIC3 Catherine Snow Publications for gene: ZIC3 were set to
CAKUT v1.59 ZIC3 Catherine Snow Classified gene: ZIC3 as Green List (high evidence)
CAKUT v1.59 ZIC3 Catherine Snow Added comment: Comment on list classification: ZIC3 identified by expert review for the CAKUT panel. ZIC3 is associated with VATER/VACTERL. Renal malformations is a phenotype of this disorder. Phenotypic spectrum of ZIC3 mutation carriers is quite variable, with incomplete penetrance in males however sufficient number of unrelated cases with renal malformations for this to be classed as Green.
CAKUT v1.59 ZIC3 Catherine Snow Gene: zic3 has been classified as Green List (High Evidence).
CAKUT v1.58 GREB1L John Sayer reviewed gene: GREB1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 29220675, 29100091; Phenotypes: renal agenesis, uterus agenesis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
CAKUT v1.58 BMP4 Rebecca Foulger commented on gene: BMP4: Kept rating as Amber following agreement from Helen Brittain, Genomics England Clinical Team: evidence is borderline and. further cases or supportive evidence is needed to be confident of a causal link. Rated Amber but can be re-assessed by GLH groups at a future date.
CAKUT v1.58 CENPF Rebecca Foulger commented on gene: CENPF: Kept rating as Amber following agreement from Helen Brittain, Genomics England Clinical Team: the evidence for a congenital renal anomaly is borderline, and in view of two families only, Amber is appropriate until further families are identified.
CAKUT v1.58 CEP55 Rebecca Foulger Classified gene: CEP55 as Green List (high evidence)
CAKUT v1.58 CEP55 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Gene was added to the panel and rated Green by Zornitza Stark. 3 separate variants from 3 different ethnic groups (2 of the variants are likely Founder variants), plus zebrafish model. Most homozygous nonsense variants are embryonic lethal but PMID:28295209 report viable compound het missense variants.
CAKUT v1.58 CEP55 Rebecca Foulger Gene: cep55 has been classified as Green List (High Evidence).
CAKUT v1.57 CEP55 Rebecca Foulger Phenotypes for gene: CEP55 were changed from Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly, 236500 to Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly, 236500; MARCH syndrome; Meckel-like syndrome; lethal CEP55-related syndromes
CAKUT v1.56 CEP55 Rebecca Foulger Publications for gene: CEP55 were set to 30622327; 28264986
CAKUT v1.55 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:32100459 (Barrie et al., 2020) describe 7 individuals from 5 families with biallelic CEP55 variants. This is the first reported case of missense variants in CEP55 (Previously only a prenatal lethal phenotype was reported due to homozygous CEP55 nonsense variants). The authors suggest that compound het cases with nonsense and missense CEP55 variants have a different viable phenotype. Homozgyosity for a splice variant in CEP55 is compatible with life. Renal abnormality was reported in Patient 3.
CAKUT v1.55 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:28295209. Bondeson et al report a Swedish couple with 2 affected male fetuses homozygous for CEP55 p.Arg86*. Although the phenotype differed between fetuses, both exhibited kidney phenotypes (including renal dysplaisa). Segregation analysis supported the gene:disease association, and Haplotype analysis suggested a founder effect.
CAKUT v1.55 CEP55 Rebecca Foulger Publications for gene: CEP55 were set to 30622327
CAKUT v1.54 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:28264986: Frosk et al, 2017 report a Dutch-German Mennonite family with 3 affected fetuses homozygous for CEP55 nonsense variant p.Ser425* presenting with MIM:236500 including renal dysplasia.
CAKUT v1.54 CEP55 Rebecca Foulger commented on gene: CEP55
CAKUT v1.54 CEP55 Rebecca Foulger Phenotypes for gene: CEP55 were changed from Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly, MIM# 236500 to Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly, 236500
CAKUT v1.53 CENPF Rebecca Foulger Classified gene: CENPF as Amber List (moderate evidence)
CAKUT v1.53 CENPF Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. Gene was added to panel and rated Green by Zornitza Stark. Although CENPF has 'probable' disease confidence in Gene2Phenotype for Stromme syndrome, there are sufficient cases in OMIM and the literature to support the gene:disease association. Hydronephrosis/renal hypoplasia is seen in at least 2 Stromme families, but the phenotype is variable. CENPF is Green on the 'Renal ciliopathies' panel (Panel #725, V1.12). Rated as Amber awaiting further clinical feedback.
CAKUT v1.53 CENPF Rebecca Foulger Gene: cenpf has been classified as Amber List (Moderate Evidence).
CAKUT v1.52 CENPF Rebecca Foulger commented on gene: CENPF: PMID:26820108 (Filges et al., 2016) describe long-term clinical follow up for siblings reported by Stromme et al. (1993) with intestingal atresia, ocular anomalis and microcephaly. They detect truncating compound het variants in CENPF in the original family (Family A) and an additional sibling pair (Family B). The original siblings (Family A) had normal renal newborn ultrasounds. The additional siblings (Family B) had Hydronephrosis/bilateral renal hypoplasia in addition to Duodenal atresia and other gastrointestinal phenotypes.
CAKUT v1.52 CENPF Rebecca Foulger commented on gene: CENPF: PMID:25564561 (Waters et al., 2015) ientified a non-consagnuineous Caucasian kindred with 4 affected fetuses. Autopsy revealed phenotypes including Duodenal atresia and Bilateral renal hypolasia.
CAKUT v1.52 CENPF Rebecca Foulger commented on gene: CENPF: PMID:28407396 (Ozkinay et al., 2017) report a Stromme syndrome family with 2 affected individuals and a homozygous p.T1974Nfs*9 variant in CENPF. Renal phenotypes are not recorded in table 1.
CAKUT v1.52 CENPF Rebecca Foulger commented on gene: CENPF
CAKUT v1.52 CENPF Rebecca Foulger Publications for gene: CENPF were set to
CAKUT v1.51 CENPF Rebecca Foulger Phenotypes for gene: CENPF were changed from Stromme syndrome, 243605 to Stromme syndrome, 243605; bilateral renal hypoplasia; Duodenal atresia; Hydronephrosis
CAKUT v1.50 CENPF Rebecca Foulger Phenotypes for gene: CENPF were changed from Stromme syndrome, MIM#243605 to Stromme syndrome, 243605
CAKUT v1.49 BMP7 Rebecca Foulger Classified gene: BMP7 as Red List (low evidence)
CAKUT v1.49 BMP7 Rebecca Foulger Added comment: Comment on list classification: BMP7 was added to CAKUT panel and rated Red by Zornitza Stark. Updated rating from Grey to Red to match Zornitza's review: There are additional functional papers reporting a role for BMP7 in renal tissues, but only one reported family plus a mouse model.
CAKUT v1.49 BMP7 Rebecca Foulger Gene: bmp7 has been classified as Red List (Low Evidence).
CAKUT v1.48 BMP7 Rebecca Foulger commented on gene: BMP7: PMID:7590254 (Dudley et al., 1995) report that mice lacking BMP7 display severe defects confined to the developing kidney and eye (renal dysplasia and anophthalmia at birth).
CAKUT v1.48 BMP7 Rebecca Foulger commented on gene: BMP7
CAKUT v1.48 ISL1 Rebecca Foulger gene: ISL1 was added
gene: ISL1 was added to CAKUT. Sources: Literature
Mode of inheritance for gene: ISL1 was set to Unknown
Publications for gene: ISL1 were set to 23641053
Phenotypes for gene: ISL1 were set to CAKUT
Review for gene: ISL1 was set to RED
Added comment: Added ISL1 to panel as a Red gene, based on PMID:23641053 which show that conditional deletion of Isl1 in mice caused kidney agenesis or hypoplasia and hydroureter, a phenotype resembling human congenital anomalies of the kidney and urinary tract (CAKUT). No further literature evidence at this time to increase rating.
Sources: Literature
CAKUT v1.47 BMP4 Rebecca Foulger Classified gene: BMP4 as Amber List (moderate evidence)
CAKUT v1.47 BMP4 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on a number of papers linking BMP4 variants and renal phenotypes. Penetrance isn't complete (PMID:18305125), and phenotype is variable, even within families (PMID:30568244). However a mouse model supports a renal phenotype, and functional evidence shows expression in renal tissues. Therefore rated Amber awaiting further clinical review.
CAKUT v1.47 BMP4 Rebecca Foulger Gene: bmp4 has been classified as Amber List (Moderate Evidence).
CAKUT v1.46 BMP4 Rebecca Foulger Added comment: Comment on phenotypes: Not currently associated with a renal phenotype in OMIM or Gene2Phenotype.
CAKUT v1.46 BMP4 Rebecca Foulger Phenotypes for gene: BMP4 were changed from to CAKUT; renal maldevelopment; congenital renal dysplasia; Congenital Anomaly of the Kidneys and Urinary Tract
CAKUT v1.45 BMP4 Rebecca Foulger Publications for gene: BMP4 were set to
CAKUT v1.44 BMP4 Rebecca Foulger Mode of inheritance for gene: BMP4 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
CAKUT v1.43 BMP4 Rebecca Foulger commented on gene: BMP4: Additional mouse model in PMID:18233958 where mutant mice result in uropathies resembling human CAKUT.
CAKUT v1.43 BMP4 Rebecca Foulger commented on gene: BMP4: PMID:30568244 (Nixon et al., 2019) investigate a BMP4 variant ( c. 130G>T, p.(Gly44Ter) with segregated in a family with Stickler syndrome. One male (age 20) also had congenital renal dysplasia. No other family members reported kidney disease.
CAKUT v1.43 BMP4 Rebecca Foulger changed review comment from: PMID:18305125 (Weber et al., 2008) report 3 BMP4 variants in 5 unrelated Renal hypodysplasia (RH) patients (Ser91Cys, heterozygous in patients 6 and 7; Thr116Ser, heterozygous in patient 8; Asn150Lys, heterozygous in patient 9 and homozygous in patient 10). Patients were from Poland, Germany and Turkey. The father of patient 7 also had the variant but had normal renal ultrasound. The inheritance may be polygenic: the authors show expression of BMP4 in human renal tissue. PMID:19685083 (Tabatabaeifar et al., 2009) report functional evidence for these three missense mutations, and provide in vitro functional evidence in human cell lines that BMP4 mRNA is reduced in the mutants. ; to: PMID:18305125 (Weber et al., 2008) report 3 BMP4 variants in 5 unrelated CAKUT patients (Ser91Cys, heterozygous in patients 6 and 7; Thr116Ser, heterozygous in patient 8; Asn150Lys, heterozygous in patient 9 and homozygous in patient 10). Patients were from Poland, Germany and Turkey. All five affected patients presented with a spectrum of renal maldevelopment, ranging from kidney agenesis to hypoplasia and dysplasia (with or without
cysts). The father of patient 7 also had the variant but had normal renal ultrasound. The inheritance may be polygenic: the authors show expression of BMP4 in human renal tissue. PMID:19685083 (Tabatabaeifar et al., 2009) report functional evidence for these three missense mutations, and provide in vitro functional evidence in human cell lines that BMP4 mRNA is reduced in the mutants.
CAKUT v1.43 BMP4 Rebecca Foulger changed review comment from: PMID:18305125 (Weber et al., 2008) report 3 BMP4 variants in 5 unrelated Renal hypodysplasia (RH) patients (Ser91Cys, heterozygous in patients 6 and 7; Thr116Ser, heterozygous in patient 8; Asn150Lys, heterozygous in patient 9 and homozygous in patient 10). Patients were from Poland, Germany and Turkey. The father of patient 7 also had the variant but had normal renal ultrasound. The inheritance may be polygenic. the authors show expresson of BMP4 in human renal tissue.; to: PMID:18305125 (Weber et al., 2008) report 3 BMP4 variants in 5 unrelated Renal hypodysplasia (RH) patients (Ser91Cys, heterozygous in patients 6 and 7; Thr116Ser, heterozygous in patient 8; Asn150Lys, heterozygous in patient 9 and homozygous in patient 10). Patients were from Poland, Germany and Turkey. The father of patient 7 also had the variant but had normal renal ultrasound. The inheritance may be polygenic: the authors show expression of BMP4 in human renal tissue. PMID:19685083 (Tabatabaeifar et al., 2009) report functional evidence for these three missense mutations, and provide in vitro functional evidence in human cell lines that BMP4 mRNA is reduced in the mutants.
CAKUT v1.43 BMP4 Rebecca Foulger commented on gene: BMP4: PMID:18305125 (Weber et al., 2008) report 3 BMP4 variants in 5 unrelated Renal hypodysplasia (RH) patients (Ser91Cys, heterozygous in patients 6 and 7; Thr116Ser, heterozygous in patient 8; Asn150Lys, heterozygous in patient 9 and homozygous in patient 10). Patients were from Poland, Germany and Turkey. The father of patient 7 also had the variant but had normal renal ultrasound. The inheritance may be polygenic. the authors show expresson of BMP4 in human renal tissue.
CAKUT v1.43 BMP4 Rebecca Foulger commented on gene: BMP4: PMID:23641053 (Kaku et al., 2013). Indirect Animal study. Authors studied renal expression and phenotype of Isl1 in mice. Lack of Isl1 reduced the expression of mouse Bmp4.
CAKUT v1.43 BMP4 Rebecca Foulger commented on gene: BMP4
CAKUT v1.43 NADSYN1 Zornitza Stark gene: NADSYN1 was added
gene: NADSYN1 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: NADSYN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NADSYN1 were set to 31883644
Phenotypes for gene: NADSYN1 were set to Multiple congenital abnormalities; absent kidneys; cardiac; limb; vertebral
Review for gene: NADSYN1 was set to GREEN
gene: NADSYN1 was marked as current diagnostic
Added comment: Five individuals from four unrelated families.
Sources: Expert list
CAKUT v1.43 CHRNA3 Zornitza Stark gene: CHRNA3 was added
gene: CHRNA3 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: CHRNA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRNA3 were set to 31708116
Phenotypes for gene: CHRNA3 were set to CAKUT; dysautonomia
Review for gene: CHRNA3 was set to GREEN
gene: CHRNA3 was marked as current diagnostic
Added comment: Five affected individuals from three unrelated families.
Sources: Expert list
CAKUT v1.43 BNC2 Eleanor Williams Phenotypes for gene: BNC2 were changed from Posterior urethral valves; PUV; Congenital lower urinary-tract obstruction to Posterior urethral valves; PUV; Congenital lower urinary-tract obstruction; Lower urinary tract obstruction, congenital, 618612
CAKUT v1.41 WNT5A Zornitza Stark gene: WNT5A was added
gene: WNT5A was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: WNT5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: WNT5A were set to Robinow syndrome, autosomal dominant 1, MIM#180700
Review for gene: WNT5A was set to GREEN
gene: WNT5A was marked as current diagnostic
Added comment: Renal anomalies in about a quarter.
Sources: Expert list
CAKUT v1.41 VPS33B chirag patel reviewed gene: VPS33B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
CAKUT v1.41 ZIC3 Zornitza Stark gene: ZIC3 was added
gene: ZIC3 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: ZIC3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: ZIC3 were set to VACTERL association, X-linked, MIM# 314390
Review for gene: ZIC3 was set to GREEN
Added comment: Renal malformations are a feature of VACTERL.
Sources: Expert list
CAKUT v1.41 TBC1D1 chirag patel gene: TBC1D1 was added
gene: TBC1D1 was added to CAKUT. Sources: Literature
Mode of inheritance for gene: TBC1D1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBC1D1 were set to PMID: 26572137
Phenotypes for gene: TBC1D1 were set to CAKUT
Review for gene: TBC1D1 was set to GREEN
Added comment: 1 heterozygous de novo frameshift variant in TBC1D1 in 1 CAKUT.
3 further CAKUT cases with three novel or rare inherited heterozygous TBC1D1 missense variants predicted to be pathogenic. TBC1D1 mutations affected Ser237-phosphorylation or protein stability and thereby act as hypomorphs. Tbc1d1 showed widespread expression in the developing murine urogenital system. A mild CAKUT spectrum phenotype, including anomalies observed in patients carrying TBC1D1 mutations, was found in kidneys of some Tbc1d1 (-/-) mice. Significantly reduced Glut4 levels were detected in kidneys of Tbc1d1 (-/-) mice and the dysplastic kidney of a TBC1D1 mutation carrier versus controls. TBC1D1 and SLC2A4 encoding GLUT4 were highly expressed in human fetal kidney. These data demonstrate heterozygous deactivating TBC1D1 mutations in CAKUT patients with a similar renal and ureteral phenotype, and provide evidence that TBC1D1 mutations may contribute to CAKUT pathogenesis, possibly via a role in glucose homeostasis.
Sources: Literature
CAKUT v1.41 TFAP2A Zornitza Stark gene: TFAP2A was added
gene: TFAP2A was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: TFAP2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TFAP2A were set to Branchiooculofacial syndrome, MIM# 113620
Review for gene: TFAP2A was set to GREEN
Added comment: CAKUT is a feature of the phenotype.
Sources: Expert list
CAKUT v1.41 STRA6 Zornitza Stark gene: STRA6 was added
gene: STRA6 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: STRA6 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STRA6 were set to Microphthalmia, syndromic 9, MIM# 601186
Review for gene: STRA6 was set to GREEN
Added comment: Renal malformations are part of the phenotype.
Sources: Expert list
CAKUT v1.41 SLIT2 Zornitza Stark reviewed gene: SLIT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26026792; Phenotypes: CAKUT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
CAKUT v1.41 SALL4 chirag patel gene: SALL4 was added
gene: SALL4 was added to CAKUT. Sources: Literature
Mode of inheritance for gene: SALL4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SALL4 were set to PMID: 20301547
Phenotypes for gene: SALL4 were set to SALL4- related disorders
Added comment: Phenotypes include: Duane-radial ray syndrome / Okihiro syndrome; Acro-renal-ocular syndrome; and SALL4-related Holt-Oram syndrome.

Acro-renal-ocular syndrome is established clinically in individuals with the following:
-Radial ray malformations
-Renal abnormalities that can include mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesico-ureteral reflux, and bladder diverticula
-Ocular abnormalities that can include ocular coloboma and Duane anomaly
Sources: Literature
CAKUT v1.41 RRM2B Zornitza Stark reviewed gene: RRM2B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
CAKUT v1.41 ROR2 Zornitza Stark gene: ROR2 was added
gene: ROR2 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: ROR2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ROR2 were set to Robinow syndrome, autosomal recessive, MIM# 268310
Review for gene: ROR2 was set to GREEN
gene: ROR2 was marked as current diagnostic
Added comment: Although genital abnormalities are a characteristic feature, renal abnormalities described in ~10%
Sources: Expert list
CAKUT v1.41 RPGRIP1L chirag patel reviewed gene: RPGRIP1L: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
CAKUT v1.41 ROBO2 Zornitza Stark reviewed gene: ROBO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27002985, 24429398, 29194579, 31630547, 27460642; Phenotypes: CAKUT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
CAKUT v1.41 NOTCH2 chirag patel gene: NOTCH2 was added
gene: NOTCH2 was added to CAKUT. Sources: Literature
Mode of inheritance for gene: NOTCH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH2 were set to PMID: 22105858
Phenotypes for gene: NOTCH2 were set to Alagille syndrome 2; OMIM #610205
Review for gene: NOTCH2 was set to GREEN
Added comment: Renal abnormalities, both structural (small hyperechoic kidney, ureteropelvic obstruction, renal cysts) and functional (most commonly renal tubular acidosis), are found in 39% of affected individuals (73/187) [Kamath et al 2012b, Romero 2018].

Romero R. The renal sequelae of Alagille Syndrome as a Product of Altered Notch Signaling During Kidney Development. In: Kamath, BM and Loomes, KM, eds. Alagille Syndrome: Pathogenesis and Clinical Management. Cham, Switzerland: Springer Nature Switzerland AG; 2018:103-20.
Sources: Literature
CAKUT v1.41 NIPBL Zornitza Stark gene: NIPBL was added
gene: NIPBL was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: NIPBL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NIPBL were set to 8291537
Phenotypes for gene: NIPBL were set to Cornelia de Lange syndrome 1, MIM# 122470
Review for gene: NIPBL was set to GREEN
gene: NIPBL was marked as current diagnostic
Added comment: Renal abnormalities, primarily vesicoureteral reflux, have been reported in 12%
Sources: Expert list
CAKUT v1.41 MYOCD chirag patel gene: MYOCD was added
gene: MYOCD was added to CAKUT. Sources: Literature
Mode of inheritance for gene: MYOCD was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYOCD were set to PMID: 31513549
Phenotypes for gene: MYOCD were set to Megabladder; congenital heart disease; cardiomyopathy
Review for gene: MYOCD was set to GREEN
Added comment: Four unrelated families. Mono allelic disease in males (megabladder), bi-allelic disease in males and females (megabladder and congenital heart disease). Cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity.
Sources: Literature
CAKUT v1.41 LRP4 Zornitza Stark gene: LRP4 was added
gene: LRP4 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: LRP4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LRP4 were set to Cenani-Lenz syndactyly syndrome, MIM# 212780
Review for gene: LRP4 was set to GREEN
gene: LRP4 was marked as current diagnostic
Added comment: Renal hypoplasia/dysplasia is a recognised feature of this syndrome, and is a feature of the mouse model.
Sources: Expert list
CAKUT v1.41 LIFR chirag patel gene: LIFR was added
gene: LIFR was added to CAKUT. Sources: Literature
Mode of inheritance for gene: LIFR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LIFR were set to PMID: 28334964
Phenotypes for gene: LIFR were set to CAKUT
Review for gene: LIFR was set to GREEN
Added comment: 4 unrelated patients with CAKUT, including functional mouse models.

BUT gene also causes Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome with biallelic mutations.
Sources: Literature
CAKUT v1.41 KMT2D Zornitza Stark gene: KMT2D was added
gene: KMT2D was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: KMT2D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KMT2D were set to 23535010
Phenotypes for gene: KMT2D were set to Kabuki syndrome 1, MIM# 147920
Review for gene: KMT2D was set to GREEN
gene: KMT2D was marked as current diagnostic
Added comment: Renal malformations are part of the phenotype.
Sources: Expert list
CAKUT v1.41 KDM6A Zornitza Stark gene: KDM6A was added
gene: KDM6A was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: KDM6A was set to Other
Publications for gene: KDM6A were set to 23535010
Phenotypes for gene: KDM6A were set to Kabuki syndrome 2, MIM# 300867
Review for gene: KDM6A was set to GREEN
Added comment: Renal malformations are a recognised feature of this syndrome.
Sources: Expert list
CAKUT v1.41 JAG1 chirag patel gene: JAG1 was added
gene: JAG1 was added to CAKUT. Sources: Literature
Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAG1 were set to PMID: 22105858
Phenotypes for gene: JAG1 were set to Alagille syndrome 1; OMIM #118450
Review for gene: JAG1 was set to GREEN
Added comment: Renal abnormalities, both structural (small hyperechoic kidney, ureteropelvic obstruction, renal cysts) and functional (most commonly renal tubular acidosis), are found in 39% of affected individuals (73/187) [Kamath et al 2012b, Romero 2018].

Romero R. The renal sequelae of Alagille Syndrome as a Product of Altered Notch Signaling During Kidney Development. In: Kamath, BM and Loomes, KM, eds. Alagille Syndrome: Pathogenesis and Clinical Management. Cham, Switzerland: Springer Nature Switzerland AG; 2018:103-20.
Sources: Literature
CAKUT v1.41 HOXA13 Zornitza Stark gene: HOXA13 was added
gene: HOXA13 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: HOXA13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: HOXA13 were set to Hand-foot-uterus syndrome, MIM# 140000
Review for gene: HOXA13 was set to GREEN
gene: HOXA13 was marked as current diagnostic
Added comment: CAKUT is a feature of this condition, variable severity.
Sources: Expert list
CAKUT v1.41 GREB1L Zornitza Stark gene: GREB1L was added
gene: GREB1L was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GREB1L were set to 29100091
Phenotypes for gene: GREB1L were set to Renal hypodysplasia/aplasia 3, MIM# 617805
Review for gene: GREB1L was set to GREEN
gene: GREB1L was marked as current diagnostic
Added comment: At least 16 families described, and mouse model supports gene-disease association.
Sources: Expert list
CAKUT v1.41 GPC3 Zornitza Stark gene: GPC3 was added
gene: GPC3 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: GPC3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: GPC3 were set to Simpson-Golabi-Behmel syndrome, type 1 312870
Review for gene: GPC3 was set to GREEN
gene: GPC3 was marked as current diagnostic
Added comment: Nephromegaly, multicystic kidneys, hydronephrosis, hydroureter, and duplicated ureters are described features of this syndrome.
Sources: Expert list
CAKUT v1.41 FGF20 Zornitza Stark gene: FGF20 was added
gene: FGF20 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: FGF20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGF20 were set to 22698282
Phenotypes for gene: FGF20 were set to Renal hypodysplasia/aplasia 2, MIM#615721
Review for gene: FGF20 was set to AMBER
Added comment: Multiple affected fetuses in a consanguineous family; functional data.
Sources: Expert list
CAKUT v1.41 FAM58A Zornitza Stark gene: FAM58A was added
gene: FAM58A was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: FAM58A was set to Other
Publications for gene: FAM58A were set to 28225384; 18297069
Phenotypes for gene: FAM58A were set to STAR syndrome, MIM# 300707
Review for gene: FAM58A was set to GREEN
gene: FAM58A was marked as current diagnostic
Added comment: XL-dominant disorder, multiple affected families reported, renal malformation are part of the phenotype. Note deletions and sequence variants reported.
Sources: Expert list
CAKUT v1.41 EXOC3L2 chirag patel gene: EXOC3L2 was added
gene: EXOC3L2 was added to CAKUT. Sources: Literature
Mode of inheritance for gene: EXOC3L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC3L2 were set to PMID: 30327448, 28749478, 27894351
Phenotypes for gene: EXOC3L2 were set to Dandy-Walker malformation; renal dysplasia; bone marrow failure
Review for gene: EXOC3L2 was set to GREEN
Added comment: Four individuals from two unrelated families with brain, kidney and bone marrow abnormalities; another described as part of fetal autopsy series, and another in a ciliopathy cohort.
Sources: Literature
CAKUT v1.41 DHCR7 Zornitza Stark edited their review of gene: DHCR7: Changed rating: GREEN
CAKUT v1.41 DHCR7 Zornitza Stark gene: DHCR7 was added
gene: DHCR7 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: DHCR7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHCR7 were set to 3812577; 10069707; 23059950; 9678700
Phenotypes for gene: DHCR7 were set to Smith-Lemli-Opitz syndrome, MIM# 270400
gene: DHCR7 was marked as current diagnostic
Added comment: Approximately 25% of affected individuals have renal anomalies, most commonly renal hypoplasia or agenesis, renal cortical cysts, hydronephrosis, and structural anomalies of the collecting system [Curry et al 1987, Ryan et al 1998, Kratz & Kelley 1999, Nowaczyk et al 2001].
Sources: Expert list
CAKUT v1.41 CTU2 Zornitza Stark gene: CTU2 was added
gene: CTU2 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 27480277; 26633546; 31301155
Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, MIM#618142
Review for gene: CTU2 was set to GREEN
gene: CTU2 was marked as current diagnostic
Added comment: Multiple families reported though some share the same founder variant.
Sources: Expert list
CAKUT v1.41 CHD1L Zornitza Stark reviewed gene: CHD1L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: CAKUT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
CAKUT v1.41 CEP55 Zornitza Stark gene: CEP55 was added
gene: CEP55 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: CEP55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP55 were set to 30622327
Phenotypes for gene: CEP55 were set to Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly, MIM# 236500
Review for gene: CEP55 was set to GREEN
gene: CEP55 was marked as current diagnostic
Added comment: Three families and a zebrafish model support gene-disease association.
Sources: Expert list
CAKUT v1.41 CENPF Zornitza Stark gene: CENPF was added
gene: CENPF was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: CENPF was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CENPF were set to Stromme syndrome, MIM#243605
Review for gene: CENPF was set to GREEN
Added comment: Renal hypodysplasia and hydronephrosis are a feature of this syndrome.
Sources: Expert list
CAKUT v1.41 BMP7 Zornitza Stark gene: BMP7 was added
gene: BMP7 was added to CAKUT. Sources: Expert list
Mode of inheritance for gene: BMP7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP7 were set to 24429398; 7590254
Phenotypes for gene: BMP7 were set to CAKUT
Review for gene: BMP7 was set to RED
Added comment: Single patient reported in a large series; mouse model supports pathogenicity.
Sources: Expert list
CAKUT v1.41 BMP4 Zornitza Stark reviewed gene: BMP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 30568244, 24131739, 23641053, 19685083; Phenotypes: CAKUT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
CAKUT v1.41 Ellen McDonagh Panel types changed to Rare Disease 100K
CAKUT v1.40 ANOS1 Eleanor Williams Added comment: Comment on mode of inheritance: Updating the MOI to X-LINKED: hemizygous mutation in males, biallelic mutations in females. This MOI has proposed by an expert reviewer and agrees with that found in OMIM. PMID: 15001591 - reports only male cases with ANOS1 variants, with female carriers, PMID: 11297579 - reports male cases and states that obligate female carriers in families with KAL mutations have no discernible phenotype.
CAKUT v1.40 ANOS1 Eleanor Williams Mode of inheritance for gene: ANOS1 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
CAKUT v1.37 BNC2 Louise Daugherty Classified gene: BNC2 as Green List (high evidence)
CAKUT v1.37 BNC2 Louise Daugherty Added comment: Comment on list classification: Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
CAKUT v1.37 BNC2 Louise Daugherty Gene: bnc2 has been classified as Green List (High Evidence).
CAKUT v1.36 BNC2 Louise Daugherty Added comment: Comment on publications: added publication to support upgrading gene to green
CAKUT v1.36 BNC2 Louise Daugherty Publications for gene: BNC2 were set to
CAKUT v1.35 BNC2 Louise Daugherty Phenotypes for gene: BNC2 were changed from Posterior urethral valves; PUV to Posterior urethral valves; PUV; Congenital lower urinary-tract obstruction
CAKUT v1.34 BNC2 Louise Daugherty Tag watchlist was removed from gene: BNC2.
CAKUT v1.34 BNC2 Louise Daugherty edited their review of gene: BNC2: Added comment: New publication PMID: 31051115 Kolvenbach CM et al., (2019) supports the rating of this gene from Amber to Green. Though exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853∗]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.; Changed rating: GREEN
CAKUT v1.34 RET Eleanor Williams Phenotypes for gene: RET were changed from Renal Adysplasia; Multiple endocrine neoplasia IIA, 171400Medullary thyroid carcinoma, 155240Multiple endocrine neoplasia IIB, 162300Central hypoventilation syndrome, congenital, 209880Pheochromocytoma, 171300Renal agenesis, 191830{Hirschsprung disease, susceptibility to, 1}, 142623 to Renal Adysplasia; Multiple endocrine neoplasia IIA, 171400; Medullary thyroid carcinoma, 155240; Multiple endocrine neoplasia IIB, 162300; Central hypoventilation syndrome, congenital, 209880; Pheochromocytoma, 171300; Renal agenesis, 191830; {Hirschsprung disease, susceptibility to, 1}, 142623
CAKUT v1.33 NPHP3 Eleanor Williams Phenotypes for gene: NPHP3 were changed from Nephronophthisis 3, 604387Renal-hepatic-pancreatic dysplasia 1, 208540Meckel syndrome 7, 267010; Renal-Hepatic-Pancreatic Dysplasia to Nephronophthisis 3, 604387; Renal-hepatic-pancreatic dysplasia 1, 208540; Meckel syndrome 7, 267010; Renal-Hepatic-Pancreatic Dysplasia
CAKUT v1.32 EYA1 Eleanor Williams Phenotypes for gene: EYA1 were changed from Branchiootorenal syndrome 1, with or without cataracts, 113650Anterior segment anomalies with or without cataract, 113650Branchiootic syndrome 1, 602588Otofaciocervical syndrome, 166780; Branchiootorenal Spectrum Disorders to Branchiootorenal syndrome 1, with or without cataracts, 113650; Anterior segment anomalies with or without cataract, 113650; Branchiootic syndrome 1, 602588; Otofaciocervical syndrome, 166780; Branchiootorenal Spectrum Disorders
CAKUT v1.31 BSND Eleanor Williams Phenotypes for gene: BSND were changed from Bartter syndrome, type 4a, 602522Sensorineural deafness with mild renal dysfunction, 602522 to Bartter syndrome, type 4a, 602522; Sensorineural deafness with mild renal dysfunction, 602522
CAKUT v1.30 AGTR1 Eleanor Williams Phenotypes for gene: AGTR1 were changed from Renal Tubular Dysgenesis; Hypertension, essential, 145500Renal tubular dysgenesis, 267430 to Renal Tubular Dysgenesis; Hypertension, essential, 145500; Renal tubular dysgenesis, 267430
CAKUT v1.28 Ellen McDonagh Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual
CAKUT v1.27 BNC2 Louise Daugherty Tag watchlist tag was added to gene: BNC2.
CAKUT v1.27 BNC2 Louise Daugherty Classified gene: BNC2 as Amber List (moderate evidence)
CAKUT v1.27 BNC2 Louise Daugherty Added comment: Comment on list classification: New gene added by external reviewer. Changed from Red to Amber and added tag watchlist. Awaiting publication before making gene green.
CAKUT v1.27 BNC2 Louise Daugherty Gene: bnc2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.26 BNC2 Louise Daugherty Phenotypes for gene: BNC2 were changed from PUV to Posterior urethral valves; PUV
CAKUT v1.25 BNC2 Detlef Bockenhauer gene: BNC2 was added
gene: BNC2 was added to CAKUT. Sources: Other
Mode of inheritance for gene: BNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BNC2 were set to PUV
Penetrance for gene: BNC2 were set to Complete
Mode of pathogenicity for gene: BNC2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: BNC2 was set to RED
Added comment: BNC2 was presented at the European Society of Paediatric Nephrology meeting in October 2018 as a new disease gene causing posterior urethral valves (PUV) by Dr Alina Hilger from Bonn, Germany. It was identified in 3 families affected by PUV. A publication is reportedly submitted.
Sources: Other
CAKUT v1.25 ISCA-37432-Loss Louise Daugherty Region: ISCA-37432-Loss was added
Region: ISCA-37432-Loss was added to CAKUT. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37432-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37432-Loss were set to RCAD syndrome; utero-vaginal atresia; Schizophrenia; 614527; delayed development, intellectual disability; Renal cysts and diabetes syndrome; Autism Spectrum Disorder; Mayer-Rokitansky-Kster-Hauser (MRKH) syndrome in females; Chromosome 17q12 deletion syndrome; global developmental delay
CAKUT GREM1 Olivia Niblock reviewed GREM1
CAKUT PBX1 Olivia Niblock marked PBX1 as ready
CAKUT PBX1 Olivia Niblock classified PBX1 as green
CAKUT PBX1 Olivia Niblock classified PBX1 as amber
CAKUT PBX1 Olivia Niblock added PBX1 to panel
CAKUT PBX1 Olivia Niblock reviewed PBX1
CAKUT KYNU Ellen McDonagh classified KYNU as green
CAKUT HAAO Ellen McDonagh classified HAAO as green
CAKUT DACT1 Louise Daugherty added DACT1 to panel
CAKUT DACT1 Louise Daugherty reviewed DACT1
CAKUT KYNU Ellen McDonagh classified KYNU as amber
CAKUT KYNU Ellen McDonagh added KYNU to panel
CAKUT KYNU Ellen McDonagh reviewed KYNU
CAKUT HAAO Ellen McDonagh classified HAAO as amber
CAKUT HAAO Ellen McDonagh added HAAO to panel
CAKUT HAAO Ellen McDonagh reviewed HAAO
CAKUT CHD1L Ellen McDonagh classified CHD1L as red
CAKUT CHD1L Ellen McDonagh added CHD1L to panel
CAKUT CHD1L Ellen McDonagh reviewed CHD1L
CAKUT KAL1 Louise Daugherty commented on KAL1
CAKUT TBX18 John Sayer reviewed TBX18
CAKUT PAX2 John Sayer reviewed PAX2
CAKUT HNF1B John Sayer reviewed HNF1B