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Skeletal dysplasia

Gene: GZF1

Amber List (moderate evidence)

GZF1 (GDNF inducible zinc finger protein 1)
EnsemblGeneIds (GRCh38): ENSG00000125812
EnsemblGeneIds (GRCh37): ENSG00000125812
OMIM: 613842, Gene2Phenotype
GZF1 is in 6 panels

4 reviews

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Third family reported.
Created: 11 Oct 2020, 3:48 a.m. | Last Modified: 11 Oct 2020, 3:48 a.m.
Panel Version: 2.21

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Joint laxity, short stature, and myopia, MIM# 617662; Larsen-like syndrome

Publications

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

Tracy Lester (Genetics laboratory, Oxford UK)

I don't know

Not listed in SD nosology paper but phenotype includes short stature. Only 2 families?; Review on behalf of Tracy Lester
Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Larsen syndrome

Publications

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Leaving the rating as amber for now, but with a recommendation of green following GMS review.
Created: 20 Jan 2021, 11:22 p.m. | Last Modified: 20 Jan 2021, 11:22 p.m.
Panel Version: 2.68
Associated with Joint laxity, short stature, and myopia #617662 (AR) in OMIM.

As reported by Zornitza Stark, PMID: 33009817 (Zeng et al 2020) reported two Chinese sisters who presented with severe myopia, scoliosis and hearing loss. Using WES they identified two compound heterozygous variants in GZF1 (c.397400del, p. Leu133fs; c.1474del, p. Met492fs). The parents were heterozygous carriers of the variants. Functional data showed decreased levels of HA‐tagged M492fs‐GZF1 protein and no HA-tagged L133fs‐GZF1 protein or the control vector. HA‐tagged M492fs‐GZF1 protein was also localized to the cytoplasm rather than the nuclei in which wild type protein was found.

This now brings the case number to 3.
Created: 20 Jan 2021, 11:21 p.m. | Last Modified: 20 Jan 2021, 11:21 p.m.
Panel Version: 2.67
Comment on list classification: Demoting from green to amber. 2 cases plus functional data, but the functional data does not strongly support a skeletal phenotype.
Created: 20 Sep 2019, 1:51 p.m. | Last Modified: 20 Sep 2019, 1:51 p.m.
Panel Version: 1.202
Associated with Joint laxity, short stature, and myopia (#617662) in OMIM and with LARSEN SYNDROME (probable) in Gene2Phenotype. Generalized joint laxity is listed as a phenotype for Larsen syndrome in Gene2Phenotype.

PMID: 28475863 - Patel et al 2017 - 2 cases. Family 1 - a multiplex consanguineous Saudi family affected by severe and recurrent large joint dislocation and severe myopia. The index patient also had severe kyphoscoliosis. Both the index patient and her brother had short stature. A homozygous truncating variant in GZF1 was identified (c.865G>T (pGlu289∗). Family 2 - another multiplex consanguineous family affected by severe myopia, retinal detachment, and milder skeletal involvement (generalized joint laxity) A second homozygous truncating GZF1 variant was identified (c.1054dup (p.Thr352Asnfs∗50). Neither variant was present in 2,379 Saudi exomes or the Exome Aggregation Consortium (ExAC) Browser. In functional studies they found using immunofluorescence, strong localization of GZF1 in the developing mouse eye and, to a lesser extent, in the mesenchyme of the developing mouse limb buds. Using 3 patient-derived lymphoblastoid cell lines they found 1,095 genes to be dysregulated in affected individuals.
Created: 16 Jul 2019, 10:02 a.m. | Last Modified: 16 Jul 2019, 10:02 a.m.
Panel Version: 1.166
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: GZF1; Initial rating suggestion: amber
Created: 6 Mar 2019, 11:36 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
joint laxity, short stature, and myopia OMIM:617662; joint laxity, short stature, and myopia MONDO:0060556

Publications

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Not associated with phenotype in OMIM, but is a probable association in G2P. At least 2 variants reported in two multiplex consanguineous Saudi family affected by severe and recurrent large joint dislocation and severe myopia. Functional studies revealed that GZF1 is expressed in the affected tissues and that truncating variants are associated with a global transcriptional dysregulation that might hint at the disease pathogenesis (PMID 28475863)
Created: 4 Sep 2017, 9:43 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Larsen syndrome

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • NHS GMS
  • Literature
Phenotypes
  • Larsen syndrome
  • joint laxity, short stature, and myopia OMIM:617662
  • joint laxity, short stature, and myopia MONDO:0060556
Tags
for-review
OMIM
613842
Clinvar variants
Variants in GZF1
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

4 Feb 2021, Gel status: 2

Added Tag

Ivone Leong (Genomics England Curator)

Tag for-review tag was added to gene: GZF1.

20 Jan 2021, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: GZF1 were changed from Larsen syndrome to Larsen syndrome; joint laxity, short stature, and myopia OMIM:617662; joint laxity, short stature, and myopia MONDO:0060556

20 Jan 2021, Gel status: 2

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: GZF1 were set to 28475863

20 Jan 2021, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: gzf1 has been classified as Amber List (Moderate Evidence).

20 Sep 2019, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: gzf1 has been classified as Amber List (Moderate Evidence).

17 Jul 2019, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: gzf1 has been classified as Green List (High Evidence).

17 Jul 2019, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: gzf1 has been classified as Amber List (Moderate Evidence).

6 May 2019, Gel status: 4

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Added phenotypes Larsen syndrome for gene: GZF1

6 Mar 2019, Gel status: 3

Added New Source, Status Update

Eleanor Williams (Genomics England Curator)

Source NHS GMS was added to GZF1. Rating Changed from Green List (high evidence) to Green List (high evidence)

4 Sep 2017, Gel status: 4

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

4 Sep 2017, Gel status: 0

Added New Source

Sarah Leigh (Genomics England Curator)

GZF1 was added to Unexplained skeletal dysplasiapanel. Sources: Literature

4 Sep 2017, Gel status: 0

Created

Sarah Leigh (Genomics England Curator)

GZF1 was created by sleigh