Skeletal dysplasia

Gene: GPX4

Green List (high evidence)

Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence (>3 unrelated cases) available for this gene to be promoted to GREEN rating at the next major update.

Created: 25 May 2023, 7:38 p.m. | Last Modified: 25 May 2023, 7:38 p.m.

Panel Version: 4.6

PMID:24706940 - Two unrelated cases with biallelic variants. First harboured compound heterozygous variants, inheriting one from the mother (c.587+5G>A) and the other was de novo (c.588-8_588-4del). The DNA from the deceased child (second case) was not available, but both unaffected parents harboured the same heterozygous nonsense variant (c.381C>A/ p.Tyr127Ter).

PMID:32827718 - One family with two infants who died within first week of life and both harboured homozygous variants (c.153_160del/ p.His52fs*1), while the unaffected parents were heterozygous for the same variant.

PMID:34931062 - Three individuals from two unrelated families harbouring the same homozygous variant (c.455 G>A/ p. Arg152His) and presenting with mild SSMD.

This gene has been associated with relevant phenotypes in both OMIM (MIM #250220) and Gene2Phenotype (with 'strong' rating in DD and skeletal panels).

Created: 25 May 2023, 7:35 p.m. | Last Modified: 25 May 2023, 7:35 p.m.

Panel Version: 4.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spondylometaphyseal dysplasia, Sedaghatian type, OMIM:250220

Publications

• 24706940
• 32827718
• 34931062

Green List (high evidence)

PMID: 32827718
New consaguineous family with 2x infants who died within first week of life. Homozygous frameshift variant.

Created: 3 Feb 2022, 8:03 a.m. | Last Modified: 3 Feb 2022, 8:03 a.m.

Panel Version: 2.168

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spondylometaphyseal dysplasia, Sedaghatian type MIM#250220

Publications

• 24706940
• 32827718

I don't know

Severe spondylodysplastic dysplasias gp of SD - only 2 cases reported? ; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spondylometaphyseal dysplasia, Sedaghatian type 250220

Publications

• 24706940

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, 11:08 a.m. | Last Modified: 11 Oct 2023, 11:08 a.m.

Panel Version: 4.20

Comment on list classification: Demoting from Green to Amber. 3 variants but only 2 cases.

Created: 17 Jul 2019, 1:32 p.m. | Last Modified: 17 Jul 2019, 1:32 p.m.

Panel Version: 1.190

PMID: 24706940 - Smith et al 2014 - 2 cases. Case 1 - child with Sedaghatian-type spondylometaphyseal dysplasia (SSMD) heterozygous for two rare variants in GPX4;(c.587+5G>A) was inherited from the mother, and the second (c.588-8_588-4del) was de novo; both were predicted to impact splicing of GPX4. Case 2 - DNA from the child with SSMD was not available, the two unaffected parents were found by Sanger sequencing to each carry the same heterozygous stop mutation in exon 3 of GPX4, c.381C>A, p.Tyr127*.

So 3 variants but from 2 cases. PubMed search did not find any other cases.

Created: 7 May 2019, 9:10 p.m.

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: GPX4; Initial rating suggestion: amber

Created: 6 Mar 2019, 11:36 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Comment when marking as ready: Associated with phenotype in OMIM and G2P. At least three variants reported

Created: 28 Jul 2016, 1:36 p.m.

Green List (high evidence)

Tier 1

Created: 17 Jun 2016, 8:04 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spondylometaphyseal dysplasia, Sedaghatian type 250220

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