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Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.133 WDR44 Andrew Fennell gene: WDR44 was added
gene: WDR44 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Literature
Mode of inheritance for gene: WDR44 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: WDR44 were set to PMID: 38191484
Phenotypes for gene: WDR44 were set to Ciliopathy, MONDO:0005308, WDR44-related
Review for gene: WDR44 was set to GREEN
Added comment: 11 male patients with 6 missense and 1 nonsense variant in WDR44 displaying a wide range of cognitive impairment and variable congenital anomalies associated with primary cilium dysfunction.
3 patients had renal anomalies including 1 with unilateral cystic kidney disease; and nephritis, and kidney hypoplasia resulting in renal failure in two patients.
All patients had learning difficulties with 8 labelled as intellectually disabled (mild-moderate). Other clinical features included anomalies of craniofacial, musculoskeletal, brain, and cardiac development.
WDR44 is a negative regulator of ciliogenesis. Increased binding is hypothesised to underlie the pathogenicity of WDR44 variants identified in this cohort. Functional data supported impaired ciliogenesis initiation in patient fibroblasts and a zebrafish model. A zebrafish model recapitulated the human phenotype when morphants expressed WDR44 L668S, D669N, S764F, G782C, H839R, and R733* variants. Of note, D648G or N840S did not recapitulate the phenotype in the zebrafish model.
The studies supported a GoF mechanism, but the authors could not rule out that LoF of WDR44 contributes to the ciliopathy-like phenotype observed, because protein expression data was only available for a limited number of patients.
Sources: Literature
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.131 TBX6 Chirag Patel gene: TBX6 was added
gene: TBX6 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Literature
Mode of inheritance for gene: TBX6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBX6 were set to PMID: 36112137, 36161696
Phenotypes for gene: TBX6 were set to Mayer-Rokitansky-Küster-Hauser syndrome; Combined skeletal-kidney dysplasia syndrome
Review for gene: TBX6 was set to GREEN
gene: TBX6 was marked as current diagnostic
Added comment: TBX6 encodes transcription-factor box 6, a transcription factor critical to paraxial mesoderm segmentation and somitogenesis during embryonic development. TBX6 haploinsufficiency is believed to drive the skeletal and kidney phenotypes associated with the 16p11.2 deletion syndrome.

Ma et al (2022) reported 16 rare variants in TBX6 from Mayer-Rokitansky-Küster-Hauser syndrome cohort (1 truncating, 15 VUS). They observed a significant mutational burden of TBX6 in affected individuals vs controls. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms (i.e. impaired normal splicing of TBX6 messenger RNA, decreased protein expression, perturbed transcriptional activity, and protein mislocalization). There was observed incomplete penetrance and variable expressivity in families carrying deleterious variants.

Li et al (2022) reported 7 individuals with vertebral and rib malformations and structural kidney differences associated with heterozygous TBX6 gene deletion in trans with a hypomorphic TBX6 allele or biallelic TBX6 variants.
Sources: Literature
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.129 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from Syndromic disease, MONDO:0002254; CAKUT to Neurooculorenal syndrome, MIM# 620305
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.128 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Changed phenotypes: Neurooculorenal syndrome, MIM# 620305
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.122 REN Chirag Patel Classified gene: REN as Green List (high evidence)
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.122 REN Chirag Patel Gene: ren has been classified as Green List (High Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.121 AGTR1 Chirag Patel gene: AGTR1 was added
gene: AGTR1 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Expert list
Mode of inheritance for gene: AGTR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGTR1 were set to PMID: 16116425
Phenotypes for gene: AGTR1 were set to Renal tubular dysgenesis, MIM# 267430
Review for gene: AGTR1 was set to GREEN
Added comment: Three unrelated families reported.

Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios. Absence or paucity of differentiated proximal tubules is the histopathologic hallmark of the disorder and may be associated with skull ossification defects.
Sources: Expert list
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.120 REN Chirag Patel gene: REN was added
gene: REN was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Expert list
Mode of inheritance for gene: REN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REN were set to PMID: 16116425
Phenotypes for gene: REN were set to Renal tubular dysgenesis, MIM# 267430
Review for gene: REN was set to GREEN
Added comment: Well established gene disease association.

Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios. Absence or paucity of differentiated proximal tubules is the histopathologic hallmark of the disorder and may be associated with skull ossification defects.
Sources: Expert list
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.119 AGT Chirag Patel gene: AGT was added
gene: AGT was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Expert list
Mode of inheritance for gene: AGT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGT were set to PMID: 16116425, 34234805, 33163725
Phenotypes for gene: AGT were set to Renal tubular dysgenesis, MIM# 267430
Review for gene: AGT was set to GREEN
Added comment: Well established gene-disease association, more than 10 unrelated families reported.

Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios. Absence or paucity of differentiated proximal tubules is the histopathologic hallmark of the disorder and may be associated with skull ossification defects.
Sources: Expert list
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.117 ACE Chirag Patel gene: ACE was added
gene: ACE was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Expert list
Mode of inheritance for gene: ACE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACE were set to PMID: 16116425, 22095942
Phenotypes for gene: ACE were set to Renal tubular dysgenesis, MIM# 267430
Review for gene: ACE was set to GREEN
Added comment: Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios. Absence or paucity of differentiated proximal tubules is the histopathologic hallmark of the disorder and may be associated with skull ossification defects. More than 60 families reported.
Sources: Expert list
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.114 DACT1 Paul De Fazio reviewed gene: DACT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36066768; Phenotypes: Townes-Brocks syndrome 2 MONDO:0054582; Mode of inheritance: None; Current diagnostic: yes
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.102 SIX5 Zornitza Stark Phenotypes for gene: SIX5 were changed from to Branchiootorenal syndrome 2, MIM# 610896
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.99 SIX5 Zornitza Stark changed review comment from: Multiple families reported.; to: Multiple families reported. However, association between SIX5 variants and BOR is DISPUTED by ClinGen: Association has been reported in at least 6 probands in 2 publications (17357085, 24429398), however the reported variants are high in frequency in population databases, have no evidence of pathogenicity, and/or an alternate cause of disease has later been reported (21280147). This gene-disease association is supported by protein interaction and biochemical function studies (14704431, 17357085, 11950062). While EYA1 and SIX1 gene inactivation in mice leads to ear and kidney abnormalities, two independent SIX5 mouse models have cataracts and no ear or kidney abnormalities (10802667, 10802668). In summary, there is convincing evidence disputing the association between SIX5 and autosomal dominant branchio-oto-renal syndrome.
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.99 SIX5 Zornitza Stark reviewed gene: SIX5: Rating: GREEN; Mode of pathogenicity: None; Publications: 17357085, 33624842, 20301554, 24730701, 22447252; Phenotypes: Branchiootorenal syndrome 2, MIM# 610896; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.98 GDF6 Ain Roesley reviewed gene: GDF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: syndromic CAKUT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.98 TMEM260 Zornitza Stark changed review comment from: Seven unrelated families reported.
Sources: Expert Review; to: Seven unrelated families reported. Clinical features: ventricular septal defects (12/12), mostly secondary to truncus arteriosus (10/12), elevated creatinine levels (6/12), horse-shoe kidneys (1/12) and renal cysts (1/12) in patients.
Sources: Expert Review
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.96 TMEM260 Zornitza Stark gene: TMEM260 was added
gene: TMEM260 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Expert Review
Mode of inheritance for gene: TMEM260 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM260 were set to 28318500
Phenotypes for gene: TMEM260 were set to Structural heart defects and renal anomalies syndrome, MIM# 617478
Review for gene: TMEM260 was set to AMBER
Added comment: Two unrelated families reported.
Sources: Expert Review
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.92 NADSYN1 Zornitza Stark Phenotypes for gene: NADSYN1 were changed from Multiple congenital abnormalities; absent kidneys; cardiac; limb; vertebral to Vertebral, cardiac, renal, and limb defects syndrome 3, MONDO:0030077; Vertebral, cardiac, renal, and limb defects syndrome 3, OMIM:618845
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.91 NADSYN1 Zornitza Stark edited their review of gene: NADSYN1: Changed phenotypes: Vertebral, cardiac, renal, and limb defects syndrome 3, MONDO:0030077, Vertebral, cardiac, renal, and limb defects syndrome 3, OMIM:618845
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.88 WLS Teresa Zhao gene: WLS was added
gene: WLS was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Literature
Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WLS were set to PMID: 34587386
Phenotypes for gene: WLS were set to Syndromic structural birth defects
Review for gene: WLS was set to GREEN
Added comment: - Homozygous mutations in 10 affected persons from 5 unrelated families.
- Patients had multiorgan defects, including microcephal, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects.
- The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis.
Sources: Literature
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.86 ZMYM2 Zornitza Stark Phenotypes for gene: ZMYM2 were changed from 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, MIM# 619522
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.85 ZMYM2 Zornitza Stark reviewed gene: ZMYM2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, MIM# 619522; Mode of inheritance: None
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.84 HS2ST1 Zornitza Stark gene: HS2ST1 was added
gene: HS2ST1 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Expert Review
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 Neurofacioskeletal syndrome with or without renal agenesis, MIM#619194
Review for gene: HS2ST1 was set to GREEN
Added comment: 4 individuals from 3 unrelated families reported.
Sources: Expert Review
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.81 WBP11 Zornitza Stark 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, MIM# 619227; malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.80 WBP11 Zornitza Stark edited their review of gene: WBP11: Changed phenotypes: Vertebral, cardiac, tracheoesophageal, renal, and limb defects, MIM# 619227, malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.79 WBP11 Zornitza Stark gene: WBP11 was added
gene: WBP11 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Literature
Mode of inheritance for gene: WBP11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.77 GDF6 Zornitza Stark gene: GDF6 was added
gene: GDF6 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Literature
Mode of inheritance for gene: GDF6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GDF6 were set to 32737436
Phenotypes for gene: GDF6 were set to Syndromic CAKUT
Review for gene: GDF6 was set to GREEN
Added comment: Three individuals (three families) with kidney hypodysplasia and extrarenal manifestations, two of them additionally manifesting skeletal, ocular, or auricular abnormalities. Two with same variant c.746C>A p.(Ala249Glu) and the third with c.112G>C p.(Gly38Arg). "CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development."
Sources: Literature
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.75 SON Zornitza Stark gene: SON was added
gene: SON was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Expert Review
Mode of inheritance for gene: SON was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SON were set to 27545680; 27545676; 31005274
Phenotypes for gene: SON were set to ZTTK syndrome, MIM# 617140
Review for gene: SON was set to GREEN
Added comment: ZTTK syndrome is a severe multisystem developmental disorder characterised by intellectual disability, characteristic dysmorphic facial features, hypotonia, poor feeding, poor overall growth, and eye or visual abnormalities. Most individuals also have musculoskeletal abnormalities, and some have congenital defects of the heart and urogenital system. Brain imaging usually shows developmental abnormalities such as gyral changes, cortical and/or cerebellar atrophy, and thin corpus callosum. More than 40 unrelated individuals reported.

Kidney anomalies are relatively common and include horseshoe kidney, unilateral renal hypoplasia, and renal cysts.
Sources: Expert Review
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.68 ZMYM2 Konstantinos Varvagiannis gene: ZMYM2 was added
gene: ZMYM2 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Literature
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 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
Penetrance for gene: ZMYM2 were set to unknown
Review for gene: ZMYM2 was set to GREEN
Added comment: 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.

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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
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.67 HSPA9 Zornitza Stark gene: HSPA9 was added
gene: HSPA9 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Literature
Mode of inheritance for gene: HSPA9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSPA9 were set to 26598328; 32869452
Phenotypes for gene: HSPA9 were set to Even-plus syndrome, MIM# 616854; skeletal anomalies; congenital cardiac and renal anomalies: marked small nose
Review for gene: HSPA9 was set to GREEN
Added comment: Biallelic variants in 4 individuals from 5 families. Significant skeletal features and marked nasal hypoplasia with mid-face hypoplasia. 2/5 with developmental delay and abnormalities of the corpus callosum 4/5 with congenital heart disease
Sources: Literature
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.61 CTU2 Zornitza Stark Phenotypes for gene: CTU2 were changed from Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.61 CTU2 Zornitza Stark Phenotypes for gene: CTU2 were changed from to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.53 FOXC2 Zornitza Stark Phenotypes for gene: FOXC2 were changed from Lymphedema-distichiasis syndrome with renal disease and diabetes mellitus; OMIM #153400 to Lymphedema-distichiasis syndrome with renal disease and diabetes mellitus; OMIM #153400
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.52 FOXC2 Zornitza Stark Phenotypes for gene: FOXC2 were changed from to Lymphedema-distichiasis syndrome with renal disease and diabetes mellitus; OMIM #153400
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.45 FOXC2 Chirag Patel commented on gene: FOXC2: 1 German-Irish family in which 6 affected members spanning 3 generations had lymphedema-distichiasis syndrome, and a 1-bp insertion in the FOXC2 gene. Four of the affected members also had renal disease, and 3 had type II diabetes mellitus, features not usually seen in lymphedema-distichiasis syndrome. The oldest affected member of the family was 73 years old at the time of report and was on chronic renal dialysis. One of her sons, aged 45 years, had developed proteinuria at age 32 years. Renal biopsy showed chronic sclerosing glomerulopathy and chronic tubulointerstitial nephritis. One member of the family underwent renal transplantation and, shortly thereafter, pancreatic transplantation, both with excellent results. She was 36 years old at the time of report and had distichiasis but no lymphedema.
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.45 FOXC2 Chirag Patel commented on gene: FOXC2: 1 German-Irish family in which 6 affected members spanning 3 generations had lymphedema-distichiasis syndrome, and a 1-bp insertion in the FOXC2 gene. Four of the affected members also had renal disease, and 3 had type II diabetes mellitus, features not usually seen in lymphedema-distichiasis syndrome. The oldest affected member of the family was 73 years old at the time of report and was on chronic renal dialysis. One of her sons, aged 45 years, had developed proteinuria at age 32 years. Renal biopsy showed chronic sclerosing glomerulopathy and chronic tubulointerstitial nephritis. One member of the family underwent renal transplantation and, shortly thereafter, pancreatic transplantation, both with excellent results. She was 36 years old at the time of report and had distichiasis but no lymphedema.
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.45 FOXC2 Chirag Patel reviewed gene: FOXC2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 15523639; Phenotypes: Lymphedema-distichiasis syndrome with renal disease and diabetes mellitus, OMIM #153400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.35 ACTG2 Zornitza Stark gene: ACTG2 was added
gene: ACTG2 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic_VCGS. Sources: Expert list
Mode of inheritance for gene: ACTG2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ACTG2 were set to Visceral myopathy, MIM# 155310
Review for gene: ACTG2 was set to GREEN
Added comment: Renal manifestations: megacystis, hydronephrosis.
Sources: Expert list
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.33 KIF14 Chirag Patel gene: KIF14 was added
gene: KIF14 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic_VCGS. Sources: Literature
Mode of inheritance for gene: KIF14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF14 were set to PMID: 30388224. 24128419
Phenotypes for gene: KIF14 were set to Microcephaly 20, primary, autosomal recessive, OMIM #617914; ?Meckel syndrome 12, OMIM #616258
Review for gene: KIF14 was set to GREEN
Added comment: 1 family with 2 sib fetuses with features consistent with Meckel syndrome, with KIF14 mutations which segregated with the disorder in the family


Mutations in KIF14 have previously been associated with either severe, isolated or syndromic microcephaly with renal hypodysplasia (RHD). Four families with fetuses presenting with the syndromic form and harbouring biallelic variants in KIF14. The functional analyses showed that the identified variants severely impact the activity of KIF14 and likely correspond to loss-of-function mutations. In vitro and in vivo analyses did not provide evidence of a direct role for KIF14 in ciliogenesis and suggested that loss of kif14 causes ciliopathy-like phenotypes through an accumulation of mitotic cells in ciliated tissues. Altogether, the results demonstrate that KIF14 mutations result in a severe syndrome associating microcephaly and RHD through its conserved function in cytokinesis during kidney and brain development.
Sources: Literature
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.29 EXOC3L2 Zornitza Stark gene: EXOC3L2 was added
gene: EXOC3L2 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic_VCGS. Sources: Literature
Mode of inheritance for gene: EXOC3L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC3L2 were set to 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
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.26 CEP55 Zornitza Stark gene: CEP55 was added
gene: CEP55 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic_VCGS. Sources: Expert Review
Mode of inheritance for gene: CEP55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP55 were set to 28295209; 28264986
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
Added comment: Two unrelated families and animal model.
Sources: Expert Review
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.19 WNT5A Zornitza Stark gene: WNT5A was added
gene: WNT5A was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic_VCGS. 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
Added comment: Renal anomalies in about a quarter.
Sources: Expert list
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.15 KYNU Zornitza Stark gene: KYNU was added
gene: KYNU was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic_VCGS. Sources: Expert list
Mode of inheritance for gene: KYNU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KYNU were set to 28792876
Phenotypes for gene: KYNU were set to Vertebral, cardiac, renal, and limb defects syndrome 2, MIM#617661
Review for gene: KYNU was set to GREEN
Added comment: Two unrelated individuals plus functional data.
Sources: Expert list
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.13 HAAO Zornitza Stark gene: HAAO was added
gene: HAAO was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic_VCGS. Sources: Expert list
Mode of inheritance for gene: HAAO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HAAO were set to 28792876
Phenotypes for gene: HAAO were set to Vertebral, cardiac, renal, and limb defects syndrome 1, MIM#617660
Review for gene: HAAO was set to GREEN
Added comment: Two unrelated individuals, functional data.
Sources: Expert list
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.7 COQ7 Zornitza Stark gene: COQ7 was added
gene: COQ7 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic_VCGS. Sources: Expert list
Mode of inheritance for gene: COQ7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ7 were set to 31240163; 28409910; 26084283
Phenotypes for gene: COQ7 were set to Coenzyme Q10 deficiency, primary, 8, MIM#616733
Review for gene: COQ7 was set to GREEN
Added comment: Three individuals described in the literature, renal disease prominent in at least two.
Sources: Expert list