Congenital muscular dystrophy and congenital myopathy

Gene: ZC4H2

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 3:45 p.m. | Last Modified: 2 May 2024, 3:45 p.m.

Panel Version: 0.229

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

I don't know

Comment on list classification: As reviewed by Anna Sarkozy (Great Ormond Street Hospital) and others, variants in ZC4H2 cause a clinical phenotype that includes congenital arthrogryposis, joint contractures and muscle weakness similar to what has been seen in structural myopathies. As there is sufficient number of cases, this gene can be promoted to green at the next major review.

Created: 21 Dec 2023, 2:52 p.m. | Last Modified: 21 Dec 2023, 2:52 p.m.

Panel Version: 0.192

Anna Sarkozy (Great Ormond Street Hospital) reviewing this gene on the old GMS Congenital myopathy panel notes (rated Green, MOI set as "X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)" and MOP set as "Other"): as indicated also by other reviewers, variants in this gene cause a clinical phenotype that is in differential with classic congenital myopathy and affected individuals clearly have muscle weakness similar to what seen in patients with other structural myopathies. Similar genes like ECEL1 are already included in the panel.

Created: 21 Dec 2023, 2:38 p.m. | Last Modified: 21 Dec 2023, 2:38 p.m.

Panel Version: 0.191

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Green List (high evidence)

Comment on list classification: Changed from Green to Red. Updated rating from Anna Sarkozy as a result of GLH Test Group prior to sign off

Created: 3 Dec 2019, 2:50 p.m. | Last Modified: 3 Dec 2019, 2:50 p.m.

Panel Version: 1.198

Comment on mode of inheritance: MOI changed to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as some female carriers also show signs of disease.

Created: 18 Oct 2019, 11:34 a.m. | Last Modified: 18 Oct 2019, 11:34 a.m.

Panel Version: 1.183

After review with Genomics England clinical team this gene was deemed valid to include on the congenital myopathy panel, as affected individuals clearly have muscle weakness. The majority of boys with it have a level of severity that it is onset in utero, leading to contractures. Arthrogryposis and congenital myopathy are a clinical continuum and as long as the neuromuscular group do not disagree, so should on both panels.

Created: 18 Oct 2019, 11:33 a.m. | Last Modified: 18 Oct 2019, 11:33 a.m.

Panel Version: 1.182

Comment on list classification: Changed rating from Red to Green based on recommendation from Guy's Hospital. Sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.

Created: 17 Oct 2019, 9:41 a.m. | Last Modified: 17 Oct 2019, 9:41 a.m.

Panel Version: 1.173

Gene rating and review submitted by Rachael Mein, Viapath Guy's Hospital February 2019 on on behalf of London South GLH for the GMS Neurology specialist test group.

Created: 30 Apr 2019, 10:09 a.m.

Green List (high evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Wieacker-Wolff syndrome 314580

Publications

• 23623388, 26056227

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