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Mendeliome

Gene: RBFOX2

Green List (high evidence)

RBFOX2 (RNA binding fox-1 homolog 2)
EnsemblGeneIds (GRCh38): ENSG00000100320
EnsemblGeneIds (GRCh37): ENSG00000100320
OMIM: 612149, Gene2Phenotype
RBFOX2 is in 3 panels

2 reviews

Jonathon Bradshaw (Victorian Clinical Genetics Services)

Green List (high evidence)

- PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs).

- PMID: 28991257: Same research consortium as above, an additional splice variant observed in a singleton from the CHD cohort identified as a LoF predicted heterozygous mutation.

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.

- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.

- 2x NMD-predicted de novo individuals with cardiac defects have been observed (internal data).

- ClinVar: one current pathogenic entry: c.523dup (p.Ser175fs). This patient had a complex congenital cardiac defect, choreiform movement disorder, developmental delay, a clotting disorder, intermittent cyanosis, chronic lung disease, low muscle tone, short stature and failure to gain weight, mild dysmorphisms, and mild joint laxity. Brain MRI shows a stable chronic infarction, stable cerebral volume loss, and ex-vacuo prominence of ventricles (personal communication).

- ClinGen has curated this gene. Strong association and evidence supporting LoF as a mechanism of disease with a phenotype lumping referred to as RBFOX2-related congenital heart disorder (MONDO:0100557).
Created: 9 Jan 2025, 12:26 a.m. | Last Modified: 9 Jan 2025, 12:26 a.m.
Panel Version: 1.2238

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
RBFOX2-related congenital heart disorder (MONDO:0100557)

Publications

Variants in this GENE are reported as part of current diagnostic practice

Chern Lim (Victorian Clinical Genetics Services)

I don't know

- PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs).

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.
- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.
Created: 16 May 2022, 8:30 a.m. | Last Modified: 15 Jun 2022, 5:07 a.m.
Panel Version: 1.65

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypoplastic left heart syndrome (HLHS)

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
Phenotypes
  • RBFOX2-related congenital heart disorder (MONDO:0100557)
OMIM
612149
Clinvar variants
Variants in RBFOX2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

13 Jan 2025, Gel status: 3

Set Phenotypes

Ain Roesley (Victorian Clinical Genetics Services)

Phenotypes for gene: RBFOX2 were changed from Congenital heart disease MONDO:0005453, RBFOX2-related to RBFOX2-related congenital heart disorder (MONDO:0100557)

13 Jan 2025, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: RBFOX2 were changed from Hypoplastic left heart syndrome (HLHS) MONDO:0004933 to Congenital heart disease MONDO:0005453, RBFOX2-related

12 Jan 2025, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: rbfox2 has been classified as Green List (High Evidence).

25 May 2022, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: rbfox2 has been classified as Amber List (Moderate Evidence).

25 May 2022, Gel status: 2

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: RBFOX2 were changed from Hypoplastic left heart syndrome (HLHS) to Hypoplastic left heart syndrome (HLHS) MONDO:0004933

25 May 2022, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: rbfox2 has been classified as Amber List (Moderate Evidence).

16 May 2022, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Chern Lim (Victorian Clinical Genetics Services)

gene: RBFOX2 was added gene: RBFOX2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RBFOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RBFOX2 were set to PMID: 26785492; 27670201; 27485310; 25205790; 35137168 Phenotypes for gene: RBFOX2 were set to Hypoplastic left heart syndrome (HLHS) Review for gene: RBFOX2 was set to AMBER gene: RBFOX2 was marked as current diagnostic