Limb disorders

Gene: SHH

Red List (low evidence)

Agree with Red rating, need more evidence to support gene-disease association in humans for the Preaxial polydactyly phenotype. Publications supporting a relevant phenotypes have only been demonstrated in mouse models (PMID:12032320, 12837695)

Created: 7 Nov 2018, 1:26 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Preaxial polydactyly; Polydactyly

Publications

• 12032320
• 12837695
• 25782671

Variants and duplications in the regulatory ZRS region within intron LMBR1 which affect the expression of SHH have been reviewed in gene LMBR1 on this panel.

Created: 26 Nov 2019, 3 p.m. | Last Modified: 26 Nov 2019, 3 p.m.

Panel Version: 1.127

Genomic England clinical team notes - Agree with red rating. No evidence of sequence changes in SHH itself causing limb phenotype in humans

Created: 9 Sep 2018, 7:53 p.m.

Red List (low evidence)

No publications of sequence changes in SHH itself associated with limb phenotype.

https://www.ncbi.nlm.nih.gov/pubmed/25782671 concerns 2kb deletion of a 240kb upstream regulatory region of SHH which represses transriptional activity of SHH promoter.

LMBR1 aka ZRS long range enhancer is already on panel

Created: 24 Apr 2018, 12:24 p.m.

Mode of inheritance
Unknown

Comment on list classification: Added gene to panel, for review. This gene has a role in limb development.

Created: 14 Dec 2017, 4:49 p.m.

I don't know

Mode of inheritance
Unknown

Phenotypes
preaxial polydactyly; holoprosencephaly

Publications

• PMID: 12032320
• 12837695

The only variant associated with preaxial polydactyly-hypertrichosis is 2 kb deletion located ~240 kb upstream from the SHH promoter.

Created: 5 Apr 2018, 12:29 p.m.

Comment when marking as ready: Not associated with relevant phenotype on G2P or OMIM. Single variant reported in Preaxial polydactyly type 1

Created: 12 Jul 2016, 1:02 p.m.

Comment on phenotypes: Variants in SHH associated with the following phenotypes, which are not relevant for Skeletal dysplasia: Holoprosencephaly 3 142945; Microphthalmia with coloboma 5 611638; Schizencephaly 269160; Single median maxillary central incisor 147250

Created: 12 Jul 2016, 1:01 p.m.

Comment on publications: Report of 2 kb deletion located ~240 kb upstream from the SHH promoter.

Created: 12 Jul 2016, 12:58 p.m.

Green List (high evidence)

Tier 2

Created: 17 Jun 2016, 8:08 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Petit F, et al. The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis. Eur J Hum Genet. 2016 Jan 24(1), 37-43; Holoprosencephaly 3 142945; Microphthalmia with coloboma 5 611638; Schizencephaly 269160; Single median maxillary central incisor 147250

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