Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies

Gene: SMCHD1

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.

Created: 5 Dec 2024, 5:12 p.m. | Last Modified: 5 Dec 2024, 5:12 p.m.

Panel Version: 4.40

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

Green List (high evidence)

For the purposes of testing, it makes sense to tier on a MONOALLELIC basis. For R381 referrals, detection of a single pathogenic variant in SMCHD1 would provoke further investigations to confirm a diagnosis of FSHD2, which would need to be done using other methods (methylation PCR). SMCHD1 has a digenic inheritance pattern and requires a permissive haplotype/methylation status for the FSHD1 locus (D4Z4/DUX4) in addition to a monoallelic pathogenic variant in SMCHD1. Email discussion with Rachael Mein, we decided that adding this gene to the R381 panel as monoallelic would be the best approach to ensure that this will be picked up in more speculative neuromuscular referrals.

Created: 21 Feb 2024, 10:49 a.m. | Last Modified: 21 Feb 2024, 10:49 a.m.

Panel Version: 4.30

Mode of inheritance
Other

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

Comment on list classification: Promoted from Red to Amber due to overall majority of Green reviews and clinical comments from from GLH representatives. As this is digenic, this gene has been made Amber rather than Green and tagged 'digenic'.

Created: 28 Nov 2019, 4:17 p.m. | Last Modified: 29 Nov 2019, 10:34 a.m.

Panel Version: 1.184

Green List (high evidence)

FSHD2, differential diagnosis with LGMD.

Created: 21 Oct 2019, 1:27 p.m. | Last Modified: 21 Oct 2019, 1:27 p.m.

Panel Version: 1.97

overlap LGMD phenotype

Created: 10 May 2019, 3:38 p.m.

Digenic inheritance

Created: 10 May 2019, 2:17 p.m.

Mode of inheritance
Other

Phenotypes
fascioscapulohumeral muscular dystrophy

I don't know

Review and rating from Natalie Forrester (SWGLH - Bristol Genetics) on behalf of South West GLH for GMS Neurology specialist test group.

Created: 30 Apr 2019, 11:45 a.m.

Red List (low evidence)

Only if for ddx with FSHD

Created: 30 Apr 2019, 11:24 a.m.

Mode of inheritance
Other - please specifiy in evaluation comments

Phenotypes
Fascioscapulohumeral muscular dystrophy 2, digenic, 158901

Green List (high evidence)

Digenic inheritance, SMCHD1 heterozygous mutation with permissive haplotype on DUX4. While WGS will not currently be able to fully diagnose FSHD2, detection of mutation in SCHMD1 will indicate that further testing is indicated. There is recognised clinical overlap between FSHD and LGMDs hence inclusion in this panel is indicated.

Created: 29 Mar 2019, 2:02 p.m.

Mode of inheritance
Other

Phenotypes
fascioscapulohumeral muscular dystrophy

Green List (high evidence)

In line with the recommendations from Ian Berry (Leeds Genetics Laboratory), it is recommended that the mode of inheritance for this gene should be changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown. At least 10 SMCHD1 variants in unrelated cases have been associated with Fascioscapulohumeral muscular dystrophy 2, digenic (OMIM:158901)(PMID: 23143600; 24075187;31600781).

Created: 19 Mar 2024, 12:59 p.m. | Last Modified: 19 Mar 2024, 1:01 p.m.

Panel Version: 4.30

Comment when marking as ready: Associated with phenotype in OMIM and G2P. Numerous variants reported which are digenic with permissive D4Z4 haplotype

Created: 26 Jul 2016, 1 p.m.

Comment on list classification: Digenic inheritance

Created: 26 Jul 2016, 1 p.m.

Comment on mode of inheritance: Digenic with permissive D4Z4 haplotype of DUX4, that segregates independently in families

Created: 26 Jul 2016, 12:57 p.m.

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

Phenotypes
Fascioscapulohumeral muscular dystrophy 2, digenic, OMIM:158901; facioscapulohumeral muscular dystrophy 2, MONDO:0008031

Publications

• 23143600
• 24075187
• 31600781