Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic

Gene: FOXC1

Amber List (moderate evidence)

FOXC1 (forkhead box C1)
EnsemblGeneIds (GRCh38): ENSG00000054598
EnsemblGeneIds (GRCh37): ENSG00000054598
OMIM: 601090, Gene2Phenotype
FOXC1 is in 14 panels

3 reviews

Eleanor Williams (Genomics England)

PMID: 32720677 - Ferre-Fernández et al 2020 - zebrafish knockout lines with combinations of the two orthologs of FOXC1 in zebrafish, foxc1a and foxc1b. 3 phenotypes:
1. foxc1a−/− single knockout homozygous embryos and foxc1−/− double knockout homozygous embryos - severe global vascular defects and early lethality, as well as microphthalmia, periocular edema and absence of the anterior chamber of the eye
2. fish with heterozygous loss of foxc1a combined with homozygosity for foxc1b (foxc1a+/−;foxc1b−/−) demonstrated craniofacial defects, heart anomalies and scoliosis
3. All other single and combined genotypes appeared normal.
Created: 6 Oct 2020, 3:55 p.m. | Last Modified: 6 Oct 2020, 3:55 p.m.
Panel Version: 0.4807

Phenotypes
eye and vascular development

Publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Comment when marking as ready: Appears to be a distinct association but I agree, the pathogenicity of the variants is not firmly established.
Created: 30 Sep 2020, 8:26 a.m. | Last Modified: 30 Sep 2020, 8:26 a.m.
Panel Version: 0.74

Chirag Patel (Genetic Health Queensland)

I don't know

Seven FOXC1 'pathogenic' variants in 8 CAKUT families identified through WES. All individuals carrying the FOXC1 pathogenic variants are heterozygote. There was incomplete penetrance and variable expressivity in families. None of the 7 pathogenic variants were reported before in patients with Axenfeld–Rieger syndrome, anterior segment dysgenesis, or congenital glaucoma. Two of the seven pathogenic variants are novel, i.e., they were never observed in the population database before, including the gnomAD database that collects 141,456 control individuals.34 The other five pathogenic variants, though reported in the population database, are present in less than five individuals as a heterozygote. The locations of these pathogenic variants do not cluster in the forkhead domain (where variants causing Axenfeld–Rieger syndrome or anterior segment dysgenesis are located).
NB they call them pathogenic - but no documentation of ACMG criteria used.

Previous animal studies show CAKUT in homozygous and heterozygous mice.
Created: 30 Sep 2020, 4:19 a.m. | Last Modified: 30 Sep 2020, 4:19 a.m.
Panel Version: 0.69
CAKUT not a feature of this syndrome
Created: 27 Nov 2019, 11:40 p.m. | Last Modified: 27 Nov 2019, 11:40 p.m.
Panel Version: 0.0

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital anomalies of the kidney and urinary tract (CAKUT)

Publications

History Filter Activity

30 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: foxc1 has been classified as Amber List (Moderate Evidence).

30 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: foxc1 has been classified as Amber List (Moderate Evidence).

30 Sep 2020, Gel status: 2

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: FOXC1 were changed from to Congenital anomalies of the kidney and urinary tract (CAKUT)

30 Sep 2020, Gel status: 2

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: FOXC1 were set to 32475988

30 Sep 2020, Gel status: 2

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: FOXC1 were set to

30 Sep 2020, Gel status: 2

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: FOXC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

30 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Chirag Patel (Genetic Health Queensland)

Gene: foxc1 has been classified as Amber List (Moderate Evidence).

28 Nov 2019, Gel status: 1

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: foxc1 has been classified as Red List (Low Evidence).

28 Nov 2019, Gel status: 1

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: foxc1 has been classified as Red List (Low Evidence).

17 Nov 2019, Gel status: 3

Created, Added New Source, Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: FOXC1 was added gene: FOXC1 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: FOXC1 was set to Unknown