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| 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 v1.167 | 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 |
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| 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 |
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| 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 v1.148 | 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 v1.139 | ROBO2 | Sarah Leigh Phenotypes for gene: ROBO2 were changed from Vesicoureteral reflux 2, 610878; Vesicoureteral Reflux to Vesicoureteral reflux 2 610878 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v1.48 | 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 |
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| 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 | 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 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 v1.26 | 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 |
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