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Fetal anomalies

Gene: FKBP8

Amber List (moderate evidence)
FKBP8 (FK506 binding protein 8)
EnsemblGeneIds (GRCh38): ENSG00000105701
EnsemblGeneIds (GRCh37): ENSG00000105701
OMIM: 604840, Gene2Phenotype
FKBP8 is in 1 panel

3 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Additional publication identified by Rhiannon Mellis (GOSH) describing a fetus with severe thoracolumbar scoliosis and caudal spinal cord agenesis and a homozygous (c.C572T:p.P191L) variant in FKBP8 (PMID: 29261186). Note the phenotype and MOI are distinct from other reports (PMID: 32969478).

FKBP8 remains a candidate gene and so maintaining Amber rating in anticipation of additional cases to corroborate pathogenicity.
Created: 19 May 2021, 3:34 p.m. | Last Modified: 19 May 2021, 3:34 p.m.
Panel Version: 1.658
Created: 19 May 2021, 3:34 p.m.
Last Modified: 19 May 2021, 3:34 p.m.
Panel version: 1.658

Rhiannon Mellis (Great Ormond Street Hospital)

I don't know

Boissel et al 2018 (PMID: 29261186) suggest FKBP8 as a candidate gene for a fetus (19 weeks gestation) with severe thoracolumbar scoliosis with segmentation defects. Consanguineous parents. Homozygous, predicted-damaging missense variants found in this gene on WES.

Fkpb8 mutant mice show extensive fusion of vertebrae, so the authors postulate that the segmentation defects observed in the fetus are also caused by disruption of this gene.

NB this fetus was not reported to have spina bifida, in contrast to other cases in the literature
Created: 27 Apr 2021, 6:07 p.m. | Last Modified: 27 Apr 2021, 6:07 p.m.
Panel Version: 1.641

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Vertebral segmentation defects

Publications

Created: 27 Apr 2021, 6:07 p.m.
Last Modified: 27 Apr 2021, 6:07 p.m.
Panel version: 1.641

Eleanor Williams (Genomics England Curator)

I don't know

Comment on list classification: Changing rating from red to amber. 5 cases reported with plausible disease causing variants but only the FKBP8 gene looked at.
Created: 2 Dec 2020, 6:49 p.m. | Last Modified: 2 Dec 2020, 6:49 p.m.
Panel Version: 1.120
Not associated with a phenotype in OMIM.

PMID: 32969478 - Tian et al 2020 - performed Sanger sequencing of FKBP8 on DNA samples from 472 spina bifida (SB) affected fetuses and 565 unaffected controls. 5 different rare heterozygous variants (MAF ≤ 0.001) were identified among the SB patients, while no deleterious rare variants were identified in the controls. 4 of the variants are missense, the other is a stop-gain. 2 cases were in white-Hispanic patients while the other 3 were non-white Hispanic. Functional studies showed that p.Glu140* affected FKBP8 localization to the mitochondria and impaired its interaction with BCL2 ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein level. Gene expression was studied in mouse Fkbp8-/- embryos and found to be abnormal. Previous mouse models have shown neural tube defects.

Sufficient cases to rate green, but only the FKBP8 gene looked at so perhaps some caution required while further evidence is gathered.
Sources: Literature
Created: 2 Dec 2020, 6:47 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
spina bifida HP:0002414

Publications

Created: 2 Dec 2020, 6:47 p.m.

Panel version: 1.119

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Spina bifida, HP:0002414
  • Vertebral segmentation defects
OMIM
604840
Clinvar variants
Variants in FKBP8
Penetrance
None
Publications
Panels with this gene

History Filter Activity

19 May 2021, Gel status: 2

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: FKBP8 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

19 May 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: fkbp8 has been classified as Amber List (Moderate Evidence).

19 May 2021, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: FKBP8 were changed from spina bifida HP:0002414 to Spina bifida, HP:0002414; Vertebral segmentation defects

19 May 2021, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: FKBP8 were set to 32969478

2 Dec 2020, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: fkbp8 has been classified as Amber List (Moderate Evidence).

2 Dec 2020, Gel status: 1

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

Eleanor Williams (Genomics England Curator)

gene: FKBP8 was added gene: FKBP8 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FKBP8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FKBP8 were set to 32969478 Phenotypes for gene: FKBP8 were set to spina bifida HP:0002414 Review for gene: FKBP8 was set to AMBER