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| Cystic kidney disease v9.3 | COL4A5 | Aakash Joshi reviewed gene: COL4A5: Rating: AMBER; Mode of pathogenicity: None; Publications: PMCID 11121527, PMCID 11053243, PMCID 10910213; Phenotypes: cystic renal disease; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | MUC1 | Aakash Joshi reviewed gene: MUC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMCID 11068942, PMID 24509297; Phenotypes: cystic renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | SEC61A1 | Aakash Joshi reviewed gene: SEC61A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMCID 11045796, PMID 36478640; Phenotypes: cystic renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | REN |
Aakash Joshi gene: REN was added gene: REN was added to Cystic kidney disease. Sources: Literature Mode of inheritance for gene: REN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: REN were set to PMCID 11997664 Phenotypes for gene: REN were set to cystic renal disease Penetrance for gene: REN were set to unknown Review for gene: REN was set to RED Added comment: PMCID 11997664 identified in a cohort of 702 individuals with suspected inherited renal cystic disease that 1 individual had a monoallelic pathogenic REN variant. Would suggest this provides some evidence for inclusion but would be low (Red list). Sources: Literature |
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| Cystic kidney disease v9.3 | OFD1 | Aakash Joshi changed review comment from: PMCID 11403091 identified one case where the individual presents with a non-syndromic form of renal cysts. Of note the other case reported previously reviewed PMID: 10910455 appears to be a syndromic form, therefore we can only count the one case.; to: PMCID 11403091 identified one case where the individual presents with a non-syndromic form of renal cysts. Of note the other case reported previously reviewed PMID: 10910455 appears to be a syndromic form, therefore we can only count the one case and recommend remain amber. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | OFD1 | Aakash Joshi reviewed gene: OFD1: Rating: RED; Mode of pathogenicity: None; Publications: PMCID: 11403091; Phenotypes: cystic renal disease; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | COL4A4 | Aakash Joshi changed review comment from: PMCID 10910213 had a cohort of 16 patients with Alport of which 2 unrelated individuals had cystic renal disease. It is unclear whether these individuals would be classed as AD-PKD, but they were noted to not have any extra renal features.; to: PMCID 10910213 had a cohort of 16 patients with Alport of which 2 unrelated individuals had cystic renal disease. It is unclear whether these individuals would be classed as AD-PKD, but they were noted to not have any extra renal features. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | COL4A4 | Aakash Joshi reviewed gene: COL4A4: Rating: RED; Mode of pathogenicity: None; Publications: PMCID 10910213; Phenotypes: cystic renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | CDC73 |
Aakash Joshi gene: CDC73 was added gene: CDC73 was added to Cystic kidney disease. Sources: Literature Mode of inheritance for gene: CDC73 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDC73 were set to PMCID 11748460 Phenotypes for gene: CDC73 were set to multiple renal cysts Penetrance for gene: CDC73 were set to Incomplete Review for gene: CDC73 was set to GREEN Added comment: Monoallelic CDC73 variants can be associated with variable presentation of renal cysts with 15-25% of affected individuals having renal cysts as per GeneReviews. PMCID 11748460 illustrates a case where an individual presented due to renal cysts (however was being concurrently having treatment for a jaw tumour). Sources: Literature |
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| Cystic kidney disease v9.2 | CFAP47 |
Ida Ertmanska changed review comment from: The association between CFAP47 and X-linked polycystic kidney disease was classified as Disputed on 02/10/2025 by the ClinGen Kidney Cystic and Ciliopathy Disorders Expert panel (see https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da276c83-09e0-428f-a58e-6cd3bf517d00-2025-02-10T170000.000Z). The disputing evidence relates to PMID:39698362 and includes "non-specific genetically heterogenous phenotype, missense variant with no convincing functional data" for the 3 male patients with polycystic kidney disease. 2/3 variants are common in gnomAD v4, with homozygous and numerous hemizygous individuals reported. The curation summary states that "the gene may be associated with a susceptibility phenotype that could manifest with age-dependent incomplete penetrance." There is also conflicting functional evidence: PMID: 36571501 describes a knockout 40-week-old mice model with "larger kidneys, cyst-like histological changes in the kidneys, including tubular cell vacuolation and dilatation, and they had significantly shorter cilia compared to wild types. However, another study published later reported that 10-week-old knockout mice showed no apparent histological kidney problems (PMID: 40473901)."; to: The association between CFAP47 and X-linked polycystic kidney disease was classified as Disputed on 02/10/2025 by the ClinGen Kidney Cystic and Ciliopathy Disorders Expert panel (see https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da276c83-09e0-428f-a58e-6cd3bf517d00-2025-02-10T170000.000Z). The disputing evidence relates to PMID:39698362 and includes "non-specific genetically heterogenous phenotype, missense variant with no convincing functional data" for the 3 male patients with polycystic kidney disease. 2/3 variants are common in gnomAD v4, with homozygous and numerous hemizygous individuals reported. The curation summary states that "the gene may be associated with a susceptibility phenotype that could manifest with age-dependent incomplete penetrance." There is also conflicting functional evidence: PMID: 36571501 describes a knockout 40-week-old mice model with "larger kidneys, cyst-like histological changes in the kidneys, including tubular cell vacuolation and dilatation, and they had significantly shorter cilia compared to wild types. However, another study published later reported that 10-week-old knockout mice showed no apparent histological kidney problems (PMID: 40473901)." - consistent with later onset? |
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| Cystic kidney disease v9.2 | CFAP47 |
Ida Ertmanska changed review comment from: The association between CFAP47 and X-linked polycystic kidney disease was classified as Disputed on 02/10/2025 by the ClinGen Kidney Cystic and Ciliopathy Disorders Expert panel (see https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da276c83-09e0-428f-a58e-6cd3bf517d00-2025-02-10T170000.000Z). The disputing evidence relates to PMID:39698362 and includes "non-specific genetically heterogenous phenotype, missense variant with no convincing functional data" for the 3 male patients with polycystic kidney disease. 2/3 variants are common in gnomAD v4, with homozygous and numerous hemizygous individuals reported. The curation summary states that "the gene may be associated with a susceptibility phenotype that could manifest with age-dependent incomplete penetrance." There is also conflicting functional evidence: PMID: 36401472, 36571501 describe a knockout 40-week-old mice model with "larger kidneys, cyst-like histological changes in the kidneys, including tubular cell vacuolation and dilatation, and they had significantly shorter cilia compared to wild types. However, another study published later reported that 10-week-old knockout mice showed no apparent histological kidney problems (PMID: 40473901)."; to: The association between CFAP47 and X-linked polycystic kidney disease was classified as Disputed on 02/10/2025 by the ClinGen Kidney Cystic and Ciliopathy Disorders Expert panel (see https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da276c83-09e0-428f-a58e-6cd3bf517d00-2025-02-10T170000.000Z). The disputing evidence relates to PMID:39698362 and includes "non-specific genetically heterogenous phenotype, missense variant with no convincing functional data" for the 3 male patients with polycystic kidney disease. 2/3 variants are common in gnomAD v4, with homozygous and numerous hemizygous individuals reported. The curation summary states that "the gene may be associated with a susceptibility phenotype that could manifest with age-dependent incomplete penetrance." There is also conflicting functional evidence: PMID: 36571501 describes a knockout 40-week-old mice model with "larger kidneys, cyst-like histological changes in the kidneys, including tubular cell vacuolation and dilatation, and they had significantly shorter cilia compared to wild types. However, another study published later reported that 10-week-old knockout mice showed no apparent histological kidney problems (PMID: 40473901)." |
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| Cystic kidney disease v8.15 | TMEM17 | Ida Ertmanska Added comment: Comment on list classification: There are at least 9 unrelated individuals (3 surviving individuals and 6 fetal cases) reported with biallelic TMEM17 variants and evidence of a multisystem ciliopathy (molar tooth sign, features supporting a diagnosis of Meckel syndrome, Joubert syndrome). More than 3 unrelated individuals had polycystic kidneys, as well as other renal findings. Hence, this gene should be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v8.14 | TMEM17 |
Ida Ertmanska gene: TMEM17 was added gene: TMEM17 was added to Cystic kidney disease. Sources: Literature Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM17 were set to 26982032; 32055034; 40841990; 41054827 Phenotypes for gene: TMEM17 were set to Meckel syndrome, MONDO:0018921; orofaciodigital syndrome type 6, MONDO:0010176; Joubert syndrome, MONDO:0018772 Review for gene: TMEM17 was set to GREEN Added comment: PMID: 26982032 Li et al., 2016 Homozygous missense mutation reported in TMEM17 (p.Asn102Lys) in two siblings (both male, 20 yrs and 36yrs old whose clinical profile is consistent with Oral-Facial-Digital type 6 syndrome. Both patients had polydactyly, psychomotor delay; cerebellar hypoplasia and molar tooth sign also noted on brain imaging (see S2 table). Fibroblasts from a TMEM17-mutated sibling displayed a much reduced ability to form cilia compared to cells from the healthy heterozygous mother. PMID: 32055034 Shamseldin et al., 2020 Homozygous variant NM_198276:c.302G > T; p.Gly101Val detected in a child with Joubert syndrome. PMID: 40841990 Boutaud et al., 2025 Report of two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts. Exome sequencing identified a founder homozygous missense variant c.280C>T, p.(Arg94Trp) in TMEM17. Both diagnosed with Meckel syndrome (severe ciliopathy). PMID: 41054827 Pardo et al., 2025 Four unrelated patients were identified with a clinical diagnosis of Meckel-Gruber syndrome (MGS) - a severe, lethal ciliopathy - and novel homozygous TMEM17 variants: NM_198276.3 c.4del p.(Glu2Serfs*58); c.366dup p.(Pro123Thrfs*9); and c.368C>G p.(Pro123Arg). Severe prenatal phenotype: encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality. This gene is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026). Sources: Literature |
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| Cystic kidney disease v8.11 | PDIA6 |
Ida Ertmanska gene: PDIA6 was added gene: PDIA6 was added to Cystic kidney disease. Sources: Literature Q2_26_promote_green tags were added to gene: PDIA6. Mode of inheritance for gene: PDIA6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDIA6 were set to 33495992; 34487921; 35856135; 40974269 Phenotypes for gene: PDIA6 were set to Polycystic kidney dysplasia, HP:0000113; Diabetes mellitus, HP:0000819; Microcephaly, HP:0000252 Review for gene: PDIA6 was set to GREEN Added comment: PMID: 33495992 Al-Fadhli et al 2021 Case of a child with asphyxiating thoracic dystrophy (ATD) syndrome and infantile-onset diabetes who had a homozygous frameshift variant in the PDIA6 gene (NM_001282704.1:c.703del (p.Val235fs)) which is in exon 8 (of 15). The parents and unaffected sibling were heterozygous for this variant. The authors state that PDIA6 is not known yet to be involved in the formation or function of the primary cilia but suggest that it could be directly or indirectly interacting or required for proper protein folding of known or unknown ciliopathy protein. PMID: 35856135 De Franco et al., 2022 Report of a biallelic loss-of-function PDIA6 NM_005742:p.Tyr316* variant in a male proband with polycystic kidney disease, infancy-onset diabetes, microcephaly, developmental delay, bilateral sensorineural hearing loss, hypotonia, visual impairment, and steatorrhea. Consanguineous, Middle Eastern parents with history of pregnancy loss. PMID: 40974269 Al-Hadidi et al., 2026 Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..? Functional evidence: PMID: 34487921 Chhabra et al., 2023 Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity. PMID: 39044457 Kim et al., 2024 Study involved Pdia6 knockout mice with in a 58 bp deletion in exon 3, and a frameshift mutation in exon 4 Downregulating PDIA6 leads to cilia removal, makes cells more sensitive to ferroptotic death caused by endoplasmic reticulum (ER) stress. The reduction of PDIA6 intensifies the ER stress response, while also impairing the regulation of primary cilia in various cell types. Pdia6+/− mice displayed glomerular abnormalities that are suggestive of glomerulosclerosis Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated. Sources: Literature |
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| Cystic kidney disease v8.10 | TMEM72 | Ida Ertmanska Added comment: Comment on list classification: There are 6 families reported in literature with biallelic TMEM72 variants and a nephronophthisis phenotype. Kidney failure occurred at 21-41 years in 5 families; 1 case had prenatal-onset kidney failure. Based on available evidence, this gene should be promoted to Green for Cystic kidney disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v8.9 | TMEM72 |
Ida Ertmanska gene: TMEM72 was added gene: TMEM72 was added to Cystic kidney disease. Sources: Literature Q1_26_promote_green tags were added to gene: TMEM72. Mode of inheritance for gene: TMEM72 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM72 were set to 41308066 Phenotypes for gene: TMEM72 were set to nephronophthisis, MONDO:0019005 Review for gene: TMEM72 was set to GREEN Added comment: PMID: 41308066 Claus et al., 2025 Study identified biallelic TMEM72 variants in 9 patients from six families with a phenotype suggestive of nephronophthisis. Five families presented with kidney failure at 21-41years. Kidney ultrasound showed small-to-normal-sized kidneys, increased echogenicity and loss of corticomedullary differentiation. One patient (Family F) had a different phenotype with prenatal onset of kidney failure, as well as epilepsy and intra-uterine oligohydramnios; she died at age 2 years. Patients in families A-E were homozygous for frameshift/truncating TMEM72 variants, while proband in family F was homozygous for a missense variant c.370G>A p.(Gly124Ser). Functional evidence: in human-derived tubuloids, authors showed that TMEM72 localizes to the cilium; affinity proteomics approach showed an association of TMEM72 ciliary function in selective ciliary cholesterol transport. TMEM72 has not yet been associated with disease in OMIM or Gene2Phenotype (accessed 9th March 2026). Sources: Literature |
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| Cystic kidney disease v8.2 | CYP24A1 |
Eleanor Williams changed review comment from: The OMIM entry for this gene disease association Hypercalcemia, infantile, 1, OMIM:143880 records an autosomal recessive mode of inheritance but no publications since 2011 have been assessed. There is now evidence that individuals may present with disease in adult hood, and some evidence that those with monoallelic variants present with milder disease. Update on monallelic cases: PMID: 21675912 - Schlingmann et al 2011 - report 7 families with homozgyous or compound heterozgyous variants in CYP24A1 and infantile hypercalcaemia and 1 case with a heterozygous deletion affecting a splice site but the authors note that there may be another undetected variant outside of the coding region. Analysis was of a few candidate genes only. Renal cysts were not assessed. PMID: 22337913 - Tebben et al 2012 - proband (aged 44 years) with hypercalcemia and hypercalciuria and elevated serum 1,25(OH)2D. Only CYP24A1 and CYP27B were sequenced. 2 splice mutations in CYP24A1 were identified. Seven family members from three generations showed chemical and clinical phenotypes with one or two CYP24A1 mutations, suggesting autosomal dominant transmission with partial penetrance of the trait. Renal cysts were noted in the proband and one heterozygous child of the proband. PMID: 24235083 - Colussi et al 2014 - report 2 unrelated probands with homozgyous variants in CYP24A1 and recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)(2)D levels; heterozygous carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25(OH)(2)D (four of four). The authors conclude that heterozygous carriers may also have subtle abnormalities of vitamin D metabolism that predispose them to events such as renal stones. PMID: 26214117 - Molin et al 2015 - report 25 patients out of a pool of 72 with hypercalcemia that had CYP24A1 variants. Only this gene was screened. 20 had biallelic variants, mostly with nephrocalincosis or renal stones. 5 neonates were heterozygous without renal disease. Further investigation of relatives found a further 21 heterozygotes who were found to have normal serum calcium and PTH levels. They note that while most heterozygous individuals remain asymptomatic, hypercalcemia may occur due to excessive vitamin D intake. PMID: 27129455 - O'Keeffe et al 2016 - ABSTRACT ONLY ACCESSED - report a family with affected individuals with both biallelic and monallelic variants in CYP24A1. A gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations. However, they note that 2 subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia. PMID: 34307984 - Hanna et al 2021 - report a high prevalance in of kidney cysts in patients with CYP24A1 deficiency. Looked at 16 patients from 12 pedigrees with confirmed pathogenic variants. Medullary and/or corticomedullary junction cysts were present in all cases. Heterozygous variants were reported in 2 families - patient 11, pedigree 7, and patients 1,2 and 3 in pedigree 1. Patient 10 was compound heterozygous. Family 1 is same family reported in Tebben et al 2012. PMID: 38504242 - Wang et al 2024 - studied 6 patients with Idiopathic infantile hypercalcemia. 2 patients were found to have compound heterozygous mutations of CYP24A1, one patient had a monoallelic CYP24A1 variant (patient 1). Patient presented with hypercalcemia and had significant renal calcification. PMID: 33249478 - Brancatella et al 2021 - ABSTRACT ONLY ACCESSED - a large family harboring the nonsense c.667A>T, p.Arg223* pathogenic variant in the CYP24A1 gene was evaluated. All subjects underwent clinical and biochemical evaluation and complete analysis of vitamin D metabolites. The 40 yo male proband proband, was homozygous for p.Arg223* pathogenic variant. Compared with the wild-types, heterozygotes had higher serum calcium and 25(OH)D3 concentrations, without any difference in the other biochemical parameters and in the rate of nephrolithiasis. The authors note that heterozygotes might require surveillance because of the potential risk of developing hypercalcemia and related clinical manifestations if exposed to triggering factors. In conclusion, while the bulk of patients with Hypercalcemia have biallelic variants, those with monoallelic variants generally present with a milder phenotype, which may be amplified by exposure to high levels of vitamin D.; to: The OMIM entry for this gene disease association Hypercalcemia, infantile, 1, OMIM:143880 records an autosomal recessive mode of inheritance but no publications since 2011 have been assessed. There is now evidence that individuals may present with disease in adult hood, and some evidence that those with monoallelic variants present with milder disease. Update on monoallelic cases where a phenotype is assessed: PMID: 21675912 - Schlingmann et al 2011 - report 7 families with homozgyous or compound heterozgyous variants in CYP24A1 and infantile hypercalcaemia and 1 case with a heterozygous deletion affecting a splice site but the authors note that there may be another undetected variant outside of the coding region. Analysis was of a few candidate genes only. Renal cysts were not assessed. PMID: 22337913 - Tebben et al 2012 - proband (aged 44 years) with hypercalcemia and hypercalciuria and elevated serum 1,25(OH)2D. Only CYP24A1 and CYP27B were sequenced. 2 splice mutations in CYP24A1 were identified. Seven family members from three generations showed chemical and clinical phenotypes with one or two CYP24A1 mutations, suggesting autosomal dominant transmission with partial penetrance of the trait. Renal cysts were noted in the proband and one heterozygous child of the proband. PMID: 24235083 - Colussi et al 2014 - report 2 unrelated probands with homozgyous variants in CYP24A1 and recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)(2)D levels; heterozygous carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25(OH)(2)D (four of four). The authors conclude that heterozygous carriers may also have subtle abnormalities of vitamin D metabolism that predispose them to events such as renal stones. PMID: 26214117 - Molin et al 2015 - report 25 patients out of a pool of 72 with hypercalcemia that had CYP24A1 variants. Only this gene was screened. 20 had biallelic variants, mostly with nephrocalincosis or renal stones. 5 neonates were heterozygous without renal disease. Further investigation of relatives found a further 21 heterozygotes who were found to have normal serum calcium and PTH levels. They note that while most heterozygous individuals remain asymptomatic, hypercalcemia may occur due to excessive vitamin D intake. PMID: 27129455 - O'Keeffe et al 2016 - ABSTRACT ONLY ACCESSED - report a family with affected individuals with both biallelic and monallelic variants in CYP24A1. A gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations. However, they note that 2 subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia. PMID: 34307984 - Hanna et al 2021 - report a high prevalance in of kidney cysts in patients with CYP24A1 deficiency. Looked at 16 patients from 12 pedigrees with confirmed pathogenic variants. Medullary and/or corticomedullary junction cysts were present in all cases. Heterozygous variants were reported in 2 families - patient 11, pedigree 7, and patients 1,2 and 3 in pedigree 1. Patient 10 was compound heterozygous. Family 1 is same family reported in Tebben et al 2012. PMID: 38504242 - Wang et al 2024 - studied 6 patients with Idiopathic infantile hypercalcemia. 2 patients were found to have compound heterozygous mutations of CYP24A1, one patient had a monoallelic CYP24A1 variant (patient 1). Patient presented with hypercalcemia and had significant renal calcification. PMID: 33249478 - Brancatella et al 2021 - ABSTRACT ONLY ACCESSED - a large family harboring the nonsense c.667A>T, p.Arg223* pathogenic variant in the CYP24A1 gene was evaluated. All subjects underwent clinical and biochemical evaluation and complete analysis of vitamin D metabolites. The 40 yo male proband proband, was homozygous for p.Arg223* pathogenic variant. Compared with the wild-types, heterozygotes had higher serum calcium and 25(OH)D3 concentrations, without any difference in the other biochemical parameters and in the rate of nephrolithiasis. The authors note that heterozygotes might require surveillance because of the potential risk of developing hypercalcemia and related clinical manifestations if exposed to triggering factors. In conclusion, while the bulk of patients with Hypercalcemia have biallelic variants, those with monoallelic variants generally present with a milder phenotype or are asymptomatic, and therefore the mode of inheritance should be kept as biallelic until the association with disease is more clear. |
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| Cystic kidney disease v7.7 | CYS1 | Arina Puzriakova Entity copied from Renal ciliopathies v3.15 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v7.6 | CYP24A1 | Sarah Leigh changed review comment from: CYP24A1 variants have been associated with Hypercalcemia, infantile, 1 (OMIM:143880). PMIDs: 34307984; 22337913; 27105398; 28324001 report numerous biallelic CYP24A1 variants in cases of OMIM:143880, with the occurrence of kidney cysts. PMID: 34307984 also reports a family, where three of the members are monoallelic for CYP24A1 variants, but present with OMIM:143880 and 2/3 of these cases also have kidney cysts.; to: CYP24A1 variants have been associated with Hypercalcemia, infantile, 1 (OMIM:143880). PMIDs: 34307984; 22337913; 27105398; 28324001 report numerous biallelic CYP24A1 variants in cases of OMIM:143880, with the occurrence of kidney cysts. PMID: 34307984 also reports a family, where three of the members are monoallelic for CYP24A1 variants, but present with OMIM:143880 and 2/3 of these cases also have kidney cysts. However, as this is the only report of monoallelic variants for this gene associated with OMIM:143880, the mode of inheritance for this gene should be BIALLELIC, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v5.8 | OFD1 |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Although renal cysts are present in around half of the cases reported in PMID:11179005 (and associated with Orofaciodigital syndrome I, MIM #311200), they are syndromic cases./ As reviewed by Nour Elkhateeb, female patient reported in PMID:10910455 had renal cysts are the only apparent manifestation. Hence, this gene can be promoted from red to amber with the current evidence.; to: Comment on list classification: Although renal cysts are present in around half of the cases reported in PMID:11179005 (and associated with Orofaciodigital syndrome I, MIM #311200), they are syndromic. As reviewed by Nour Elkhateeb, female patient reported in PMID:10910455 had renal cysts are the only apparent manifestation. Hence, this gene can be promoted from red to amber with the current evidence. |
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| Cystic kidney disease v5.8 | OFD1 |
Achchuthan Shanmugasundram Added comment: Comment on list classification: Although renal cysts are present in around half of the cases reported in PMID:11179005 (and associated with Orofaciodigital syndrome I, MIM #311200), they are syndromic cases./ As reviewed by Nour Elkhateeb, female patient reported in PMID:10910455 had renal cysts are the only apparent manifestation. Hence, this gene can be promoted from red to amber with the current evidence. |
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| Cystic kidney disease v4.24 | OFD1 | Nour Elkhateeb changed review comment from: OFD1 appears to be highly penetrant, although highly variable in expression. In some reports, renal cysts are the only apparent manifestation in affected females. PMID: 10910455.; to: OFD1 appears to be highly penetrant, although highly variable in expression. In some reports, renal cysts are the only apparent manifestation in affected females. PMID: 10910455. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v4.24 | OFD1 | Nour Elkhateeb reviewed gene: OFD1: Rating: ; Mode of pathogenicity: None; Publications: PMID: 10910455; Phenotypes: renal cysts; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v4.22 | NEK8 |
Achchuthan Shanmugasundram changed review comment from: PMID:37598857 reported the identification of monoallelic NEK8 variants in 12 different families reported with autosomal dominant polycystic kidney disease (ADPKD). Of these, de novo missense variant p.Arg45Trp was found in 10 families and missense variants p.Ile150Met and p.Lys157Gln were found in one family each. Patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8. PMID:18199800 reported one patient with biallelic NEK8 variant (p.His425Tyr) and with nephronophthisis. Nephronophthisis is an autosomal recessive kidney disease that leads to kidney cyst formation and progressive renal failure. Although nephronophthisis 9 (MIM #613824) caused by biallelic variants is reported in both OMIM and Gene2Phenotype, cystic kidney disease caused by monoallelic variants are not yet reported in these resources.; to: PMID:37598857 reported the identification of monoallelic NEK8 variants in 12 different families reported with autosomal dominant polycystic kidney disease (ADPKD). Of these, de novo missense variant p.Arg45Trp was found in 10 families and missense variants p.Ile150Met and p.Lys157Gln were found in one family each. Patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8. Carriers of AR-NEK8 disease do not show renal manifestations, as variants are LOF and these variants are suspected of dominant negative effect. PMID:18199800 reported one patient with biallelic NEK8 variant (p.His425Tyr) and with nephronophthisis. Nephronophthisis is an autosomal recessive kidney disease that leads to kidney cyst formation and progressive renal failure. Although nephronophthisis 9 (MIM #613824) caused by biallelic variants is reported in both OMIM and Gene2Phenotype, cystic kidney disease caused by monoallelic variants are not yet reported in these resources. |
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| Cystic kidney disease v4.19 | NEK8 |
Achchuthan Shanmugasundram changed review comment from: PMID:37598857 reported the identification of monoallelic NEK8 variants in 12 different families reported with autosomal dominant polycystic kidney disease (ADPKD). Of these, de novo missense variant p.Arg45Trp was found in 10 families and missense variants p.Ile150Met and p.Lys157Gln were found in one family each. Patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8.; to: PMID:37598857 reported the identification of monoallelic NEK8 variants in 12 different families reported with autosomal dominant polycystic kidney disease (ADPKD). Of these, de novo missense variant p.Arg45Trp was found in 10 families and missense variants p.Ile150Met and p.Lys157Gln were found in one family each. Patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8. PMID:18199800 reported one patient with biallelic NEK8 variant (p.His425Tyr) and with nephronophthisis. Nephronophthisis is an autosomal recessive kidney disease that leads to kidney cyst formation and progressive renal failure. Although nephronophthisis 9 (MIM #613824) caused by biallelic variants is reported in both OMIM and Gene2Phenotype, cystic kidney disease caused by monoallelic variants are not yet reported in these resources. |
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| Cystic kidney disease v4.15 | SEC63 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Ian Berry, this gene should be considered for green rating in this panel in the next GMS review as there are sufficient cases of polycystic liver disease 2 with both renal and hepatic cysts. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v4.10 | PRKCSH | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Ian Berry, this gene should be considered for green rating in this panel in the next GMS review as there are sufficient cases of polycystic liver disease 1 with renal cysts.; to: Comment on list classification: As reviewed by Ian Berry, this gene should be considered for green rating in this panel in the next GMS review as there are sufficient cases of polycystic liver disease 1 with both renal and hepatic cysts. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v4.7 | PRKCSH | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Ian Berry, this gene should be considered for green rating in this panel in the next GMS review as there are sufficient cases of polycystic liver disease 1 with renal cysts. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v4.6 | PRKCSH |
Ian Berry changed review comment from: Phenotype is predominantly hepatic but can involve renal cysts. We have seen 2x patients with pathogenic findings in this gene through R193 referrals therefore it makes sense to be on this panel. R193 referrals frequently have both renal & hepatic cysts.; to: Phenotype is predominantly hepatic but can involve renal cysts. We have seen 2x patients with pathogenic findings in this gene through R193 referrals therefore it makes sense to be on this panel. R193 referrals frequently have both renal & hepatic cysts. OMIM disorder name is polycystic liver disease-1 with or without kidney cysts (PCLD1) |
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| Cystic kidney disease v4.6 | SEC63 |
Ian Berry changed review comment from: Phenotype is predominantly hepatic but can involve renal cysts. We have seen 2x patients with pathogenic findings in this gene through R193 referrals therefore it makes sense to be on this panel. R193 referrals frequently have both renal & hepatic cysts.; to: Phenotype is predominantly hepatic but can involve renal cysts. We have seen 2x patients with pathogenic findings in this gene through R193 referrals therefore it makes sense to be on this panel. R193 referrals frequently have both renal & hepatic cysts. OMIM disorder name is polycystic liver disease-2 with or without kidney cysts (PCLD2) |
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| Cystic kidney disease v4.4 | TULP3 |
Achchuthan Shanmugasundram changed review comment from: PMID:35397207 reported individuals from eight unrelated families with biallelic variants in TULP3 gene, out of which individuals from six families had kidney abnormalities including presentation of kidney cysts in at least an individual from five families. In addition, experiments in TULP3 knockout zebrafish models recapitulated the phenotypes observed in patients including the kidney cysts. PMID:36276950 reported two sisters with fibrocystic renal and hepatic disease harboring a homozygous missense mutation in TULP3 (p.Arg382Trp). In addition, experiments with inner medullary collecting duct-3 cells expressing the TULP3 R382W patient variant showed that this variant had a severely reduced ability to localise membrane-associated proteins to the cilium, consistent with a loss of TULP3 function. PMID:36460032 reported two cases with biallelic variants in TULP3 (patient A: homozygous; patient B: compound heterozygous) and both had cystic kidney disease. Functional studies from mouse models also showed that knockout mice developed cystic kidney disease (PMIDs: 30799239 & 30799240).; to: PMID:35397207 reported individuals from eight unrelated families with biallelic variants in TULP3 gene, out of which individuals from six families had kidney abnormalities including presentation of kidney cysts in at least an individual from five families. In addition, experiments in TULP3 knockout zebrafish models recapitulated the phenotypes observed in patients including the kidney cysts. PMID:36276950 reported two sisters with fibrocystic renal and hepatic disease harboring a homozygous missense mutation in TULP3 (p.Arg382Trp). In addition, experiments with inner medullary collecting duct-3 cells expressing the TULP3 R382W patient variant showed that this variant had a severely reduced ability to localise membrane-associated proteins to the cilium, consistent with a loss of TULP3 function. PMID:36460032 reported two cases with biallelic variants in TULP3 (patient A: homozygous; patient B: compound heterozygous) and both had cystic kidney disease. Functional studies from mouse models also showed that knockout mice developed cystic kidney disease (PMIDs: 30799239 & 30799240). This gene has been associated with relevant phenotypes in OMIM (MIM #619902), but not in Gene2Phenotype. |
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| Cystic kidney disease v4.3 | TULP3 | Achchuthan Shanmugasundram Phenotypes for gene: TULP3 were changed from cystic kidney disease; ductal plate malformation; congentital hepatic fibrosis; cardiomyopathy to Hepatorenocardiac degenerative fibrosis, OMIM:619902 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v4.1 | TULP3 | Achchuthan Shanmugasundram reviewed gene: TULP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30799239, 30799240, 35397207, 36276950, 36460032; Phenotypes: Hepatorenocardiac degenerative fibrosis, OMIM:619902; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v4.1 | TULP3 |
John Sayer gene: TULP3 was added gene: TULP3 was added to Cystic kidney disease. Sources: Expert list Mode of inheritance for gene: TULP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TULP3 were set to 36460032; 36276950; 35397207 Phenotypes for gene: TULP3 were set to cystic kidney disease; ductal plate malformation; congentital hepatic fibrosis; cardiomyopathy Penetrance for gene: TULP3 were set to Complete Review for gene: TULP3 was set to GREEN Added comment: TULP3 is a novel human cilipathy gene (OMIM 604730) Hepatorenocardiac degenerative fibrosis is OMIM pehnotype Cystic kidney disease is a typical feature Sources: Expert list |
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| Cystic kidney disease v2.53 | GLA | Eleanor Williams Added comment: Comment on mode of inheritance: There is evidence that heterozyous females are not always asymptomatic carriers, with renal disease being reported as part of the phenotype in several cases (PMID: 17224688 Wang et al 2007, PMID: 29770213 McCloskey et al 2018). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v2.52 | GLA | Eleanor Williams Phenotypes for gene: GLA were changed from to Fabry disease, OMIM:301500; Fabry disease, MONDO:0010526; Renal cyst, HP:0000107; renal parapelvic cysts | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v2.50 | GLA | Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with a recommendation for a green rating following GMS review. More than 3 cases reported with renal parapelvic cysts. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v2.49 | PAX2 |
Eleanor Williams changed review comment from: As reviewer notes PAX2 is associated with Papillorenal syndrome #120330 (AD) in OMIM and Renal cysts and Multicystic dysplastic kidneys are listed as clinical features. In PMID: 22213154 Bowers et al 2012 review of PAX2 variants found in patients with renal coloboma syndrome they note that renal cysts were found in 8% of patients (n = 13), and multicystic dysplastic kidneys in 6% (n = 7) from more than three unrelated families. Deng et al 2019 - PMID: 31060108 examined the phenotypes of 10 children (one was Mongolian and the rest were of Han Chinese ethnicity) with PAX2 variants. Renal cysts were detected in five patients.; to: As reviewer notes PAX2 is associated with Papillorenal syndrome #120330 (AD) in OMIM and Renal cysts and Multicystic dysplastic kidneys are listed as clinical features. In PMID: 22213154 Bowers et al 2012 review of PAX2 variants found in patients with renal coloboma syndrome they note that renal cysts were found in 8% of patients (n = 13), and multicystic dysplastic kidneys in 6% (n = 7) from more than three unrelated families. Deng et al 2019 - PMID: 31060108 examined the phenotypes of 10 children (one was Mongolian and the rest were of Han Chinese ethnicity) with PAX2 variants. Renal cysts were detected in five patients. A further case of cystic renal disease in a patient with PAX2 variants are reported in PMID: 22213154 |
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| Cystic kidney disease v2.48 | PAX2 | Eleanor Williams Phenotypes for gene: PAX2 were changed from cystic renal disease to Papillorenal syndrome, OMIM:120330; renal coloboma syndrome, MONDO:0007352 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v2.46 | PAX2 | Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber with a recommendation for green rating following GMS review. There are more than 3 cases reported where renal cysts are part of the phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v2.45 | PAX2 | Eleanor Williams reviewed gene: PAX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22213154, 31060108; Phenotypes: Papillorenal syndrome, OMIM:120330, renal coloboma syndrome, MONDO:0007352; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v2.45 | PAX2 |
Natalie Forrester gene: PAX2 was added gene: PAX2 was added to Cystic kidney disease. Sources: NHS GMS Mode of inheritance for gene: PAX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PAX2 were set to PMID: 33746522; 16049068; 22213154 Phenotypes for gene: PAX2 were set to cystic renal disease Penetrance for gene: PAX2 were set to unknown Review for gene: PAX2 was set to GREEN gene: PAX2 was marked as current diagnostic Added comment: PAX2 (OMIM 167409) is associated with Papillorenal syndrome, one feature of which can be renal cysts. Ocular involvement is common, but it is also noted that it can be mild/undetectable. In our NHSE lab we have identified a novel missense variant in a patient with cystic dysplastic kidneys. This was detected by Exomiser tiering by WGS and was reported as likely pathogenic. There are many reports in the literature of its association with renal disease, including cysts, and I expect that is the reason it is included on the R195 and R257 panels, but it also seems appropriate to be included on R193 where currently it is not even amber or red. Sources: NHS GMS |
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| Cystic kidney disease v2.45 | GLA | John Sayer reviewed gene: GLA: Rating: GREEN; Mode of pathogenicity: None; Publications: 29770213, 28371803, 27061865, 21290670, 15327390, 15091117; Phenotypes: renal parapelvic cysts, renal cortical cysts; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v2.42 | IFT140 | Eleanor Williams Added comment: Comment on mode of inheritance: As reviewer notes there are several biallelic cases reported with a renal phenotype (e.g. PMID: 23418020 - 3 patients with renal cysts and biallelic IFT140 variants, PMID: 27874174 - 1 patient with renal cysts and biallelic IFT140 variants) aswell as the monallelic variants reported in PMID:34890546 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v2.35 | DZIP1L |
Yu Leng Phua edited their review of gene: DZIP1L: Added comment: Four children from three consanguineous families presenting with polycystic kidney disease; Variants: c.193 T > C; p.(Cys65Arg), and c.216C > G; p.(Cys72Trp); Functional analyses of the c.216C > G; p.(Cys72Trp) variant indicated mislocalization of mutant DZIP1L; NOTE: Lack of liver phenotype in these patients; Changed phenotypes to: # 617610 POLYCYSTIC KIDNEY DISEASE 5, PKD5 |
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| Cystic kidney disease v2.33 | COL4A4 | Eleanor Williams commented on gene: COL4A4: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed. The reviewers note that only 1 patient reported where they would be classed as AD-PKD. The other 3 are primarily TBMN patients who also have renal cysts. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v2.27 | IFT140 |
Daniel Gale gene: IFT140 was added gene: IFT140 was added to Cystic kidney disease. Sources: Literature,Research Mode of inheritance for gene: IFT140 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IFT140 were set to 34890546 Phenotypes for gene: IFT140 were set to Cystic kidney disease; chronic kidney disease Penetrance for gene: IFT140 were set to unknown Review for gene: IFT140 was set to GREEN Added comment: Very strong evidence of association of truncating IFT140 mutations and cystic kidney disease in cited paper, which includes 12 multiplex families and 26 singletons. In addition, hypothesis-free region-based variance testing (SKAT-O) independently identifying truncating variants in this gene in 100,000 Genomes Project (p=3.5e-17) and UK BioBank (p=4.5e-15) participants with cystic kidney disease (see https://genebass.org/gene/undefined/phenotype/icd_first_occurrence-132532-both_sexes--?resultIndex=gene-manhattan&resultLayout=full for UKBB analysis). Sources: Literature, Research |
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| Cystic kidney disease v2.24 | FLCN | Eleanor Williams Phenotypes for gene: FLCN were changed from renal cysts; cutaneous fibrofolliculoma; pneumothorax; pulmonary cysts; renal cell carcinoma; renal oncocytoma to Birt-Hogg-Dube syndrome, OMIM:135150; renal cysts; cutaneous fibrofolliculoma; pneumothorax; pulmonary cysts; renal cell carcinoma; renal oncocytoma | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v2.23 | FLCN |
Daniel Gale gene: FLCN was added gene: FLCN was added to Cystic kidney disease. Sources: Literature,Expert Review Mode of inheritance for gene: FLCN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FLCN were set to PMID: 19785621; 31266032 Phenotypes for gene: FLCN were set to renal cysts; cutaneous fibrofolliculoma; pneumothorax; pulmonary cysts; renal cell carcinoma; renal oncocytoma Penetrance for gene: FLCN were set to Incomplete Review for gene: FLCN was set to GREEN Added comment: Birt Hogg Dube syndrome (caused by variants in FLCN) is frequently associated with multiple renal cysts, without renal enlargement or progressive CKD. Previous published data indicate simple renal cysts present in 31-45% (PMID: 31266032;19785621) of patients with BHD and audit of 20 patients I follow up revealed simple renal cysts in 11 (multiple in 9 of these individuals) i.e. similar to the literature. Therefore BHD should be considered in the differential diagnosis of multiple renal cysts (without renal enlargement). Sources: Literature, Expert Review |
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| Cystic kidney disease v2.0 | ALG8 |
Eleanor Williams changed review comment from: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM. PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts (1, at least 3, 3-4 and 9). 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently. PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts. Will check with the Genomics England clinical team whether the level of kidney cysts seen in Besse et al is sufficient to rate this gene green on the panel. ; to: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM. PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts (1, at least 3, 3-4 and 9). 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently. The proband with 3-4 kidney cysts has a daughter who shares the ALG8 variants and who has no liver cysts but 8 kidney cysts. PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts. |
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| Cystic kidney disease v2.0 | SEC61A1 |
Eleanor Williams changed review comment from: Associated with Hyperuricemic nephropathy, familial juvenile, 4, #617056 (AD) in OMIM. PMID: 27392076 - Bolar et al 2016 - report on two families with Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. The father in family B had multiple bilateral simple cysts throughout the kidney. In both families heterozygous missense variants in SEC61A1 were identified - c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly) -both affecting functionally important and conserved residues in SEC61. Functional studies support the renal function for this gene. PMID: 31488840- Devuyst et al 2019 - a primer that highlights the different types of ADTKD - no new cases Summary - 1 case reported with kidney cysts; to: Associated with Hyperuricemic nephropathy, familial juvenile, 4, #617056 (AD) in OMIM. PMID: 27392076 - Bolar et al 2016 - report on two families with Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. The father in family B had multiple bilateral simple cysts throughout the kidney. In both families heterozygous missense variants in SEC61A1 were identified - c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly) -both affecting functionally important and conserved residues in SEC61. Functional studies support the renal function for this gene. PMID: 31488840- Devuyst et al 2019 - a primer that highlights the different types of ADTKD - no new cases PMID: 30586318 - Groopman et al 2018 - report 1 case with a heterozygous missense variant in SEC61A1 (p.I428M). The clinical diagnosis was 'Congenital or cystic renal disease' and the genetic diagnosis 'Hyperuricemic nephropathy familial juvenile 4' (See TableS7). Summary - 2 cases reported with kidney cysts |
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| Cystic kidney disease v2.0 | ALG8 |
Eleanor Williams changed review comment from: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM. PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts. 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently. PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts. Will check with the Genomics England clinical team whether the level of kidney cysts seen in Besse et al is sufficient to rate this gene green on the panel. ; to: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM. PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts (1, at least 3, 3-4 and 9). 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently. PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts. Will check with the Genomics England clinical team whether the level of kidney cysts seen in Besse et al is sufficient to rate this gene green on the panel. |
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| Cystic kidney disease v2.0 | ALG8 |
Eleanor Williams changed review comment from: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM. PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts. 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently. PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts.; to: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM. PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts. 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently. PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts. Will check with the Genomics England clinical team whether the level of kidney cysts seen in Besse et al is sufficient to rate this gene green on the panel. |
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| Cystic kidney disease v2.0 | ALG9 |
Eleanor Williams changed review comment from: Associated with Gillessen-Kaesbach-Nishimura syndrome, 263210 (AR) in OMIM in which Polycystic kidneys is listed as a clinical feature. PMID: 31395617 - Besse et al 2019 - report 2 patients in a clinically defined cohort with genetically unresolved polycystic liver and kidney disease that had rare heterozygous loss-of-function variants in ALG9. Then using a novel ‘genotype-first’ approach to find ALG9 mutation carriers from a large cohort of exome-sequenced individuals, they found that 7/8 (88%) of ALG9 mutation carriers over age 50 had a least 4 kidney cysts (abstract only accessed). PMID: 28932688 - Davis et al 2017 - report the case of a proband with ALG9-CDG who has a milder phenotype. This female child was born to non-consanguineous parents of Scottish decent. Prenatally, dysmorphic features, numerous renal cysts and minor cardiac malformations were detected. Post-natally, dysmorphic features included shallow orbits, micrognathia, hypoplastic nipples, talipes equinovarus, lipodystrophy and cutis marmorata. She developed failure to thrive and seizures. A homozygous mutation in ALG9, c.860A > G (p.Tyr287Cys) was identified. Both parents were found to carry one copy of the mutation. In a table of phenotypic features from the 11 known patients with ALG9-CDG (including the one here), 3 other patients are reported with polycystic kidneys and homozygous ALG variants.; to: Associated with Gillessen-Kaesbach-Nishimura syndrome, 263210 (AR) in OMIM in which Polycystic kidneys is listed as a clinical feature. PMID: 31395617 - Besse et al 2019 - report 2 patients in a clinically defined cohort with genetically unresolved polycystic liver and kidney disease that had rare heterozygous loss-of-function variants in ALG9. Then using a novel ‘genotype-first’ approach to find ALG9 mutation carriers from a large cohort of exome-sequenced individuals, they found that 7/8 (88%) of ALG9 mutation carriers over age 50 had a least 4 kidney cysts (abstract only accessed). PMID: 28932688 - Davis et al 2017 - report the case of a proband with ALG9-CDG who has a milder phenotype. This female child was born to non-consanguineous parents of Scottish decent. Prenatally, dysmorphic features, numerous renal cysts and minor cardiac malformations were detected. Post-natally, dysmorphic features included shallow orbits, micrognathia, hypoplastic nipples, talipes equinovarus, lipodystrophy and cutis marmorata. She developed failure to thrive and seizures. A homozygous mutation in ALG9, c.860A > G (p.Tyr287Cys) was identified. Both parents were found to carry one copy of the mutation. In a table of phenotypic features from the 11 known patients with ALG9-CDG (including the one here), 3 other patients are reported with polycystic kidneys and homozygous ALG variants. |
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| Cystic kidney disease v1.39 | WDR19 | Anna de Burca Added comment: Comment on list classification: Promoted to green following further discussion with Ellen Thomas. Although this gene is associated with a syndromic presentation, it is appropriate for inclusion in this panel due to the renal element of the phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v1.37 | CEP83 |
Anna de Burca gene: CEP83 was added gene: CEP83 was added to Cystic kidney disease. Sources: Expert list Mode of inheritance for gene: CEP83 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CEP83 were set to 24882706 Phenotypes for gene: CEP83 were set to NEPHRONOPHTHISIS 18 Review for gene: CEP83 was set to GREEN Added comment: PMID: 24882706 reports ten variants found in biallelic form in seven families. All but one of the probands had nephronophthisis progressing to end stage renal failure; some of the affected individuals had additional features including intellectual disability and hydrocephalus. Sources: Expert list |
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| Cystic kidney disease v1.34 | DNAJB11 | Eleanor Williams Phenotypes for gene: DNAJB11 were changed from cystic kidney disease; end stage renal failure; non-enlarged kidney to cystic kidney disease; end stage renal failure; non-enlarged kidney; Polycystic kidney disease; Tubulointerstitial kidney disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v1.33 | DNAJB11 | Miranda Durkie reviewed gene: DNAJB11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29706351; Phenotypes: Polycystic kidney disease, Tubulointerstitial kidney disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v1.29 | ISCA-37432-Loss |
Louise Daugherty Region: ISCA-37432-Loss was added Region: ISCA-37432-Loss was added to Cystic kidney disease. 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 |
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