Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies

Gene: CASQ1

I don't know

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber.

The comment from the GMS reviewers is as follows:
Over the past 3 years, (when we were looking at a slightly larger gene panel (essentially R82 plus 20 genes)) we have screened more than 1000 patients on R82 and for CASQ1 have not identified any clinically significant variants.

Created: 5 Dec 2024, 5:12 p.m. | Last Modified: 5 Dec 2024, 5:24 p.m.

Panel Version: 4.40

Comment on list classification: In addition to the original founder variant, at least five other variants from this gene were identified to be associated with myopathy. There is sufficient evidence available (>20 unrelated cases and functional studies) for this gene to be promoted to GREEN at the next GMS update.

Created: 3 May 2023, 11:13 a.m. | Last Modified: 3 May 2023, 11:13 a.m.

Panel Version: 4.20

PMID:26136523 reported 10 cases from three families with the founder missense variant, pAsp244Gly and they all had benign vacuolar myopathy and hyperCKaemia.

PMID:28895244 reported the identification of three novel variants (p.Asp44Asn, p.Gly103Asp & p.Ile385Thr) in four cases with with tubular aggregate myopathy. They had fatigue and diffuse exercise-induced myalgia and the patient with p.Ile385Thr variant also had proximal muscle weakness.

PMID:29039140 reported two unrelated families with heterozygous variants (family1: p.Asn54Tyr; family 2: p.Gly103Asp). Family 1 presented between early 20s and mid-40s with a slowly progressive muscle weakness mainly involving proximal muscles in the lower limbs and family 2 presented with post-exercise myalgia in the lower limbs in early 50s.

PMID:30258016 reported 22 cases from 12 families with heterozygous variants in CASQ1. 21 of these cases shared the founder variant (p.Asp244Gly) and one had p.Gly103Asp variant. These patients usually had adult-onset exercise intolerance and myalgias and later developed slowly progressive proximal weakness with quadriceps atrophy and scapular winging. Three patients presented subclinical cardiac abnormalities and four patients had pelvic girdle weekness.

PMID:34908252 reported a case with a heterozygous missense variant p.Asp44Asn, who presented with exercise‐induced muscle spasms since childhood.

PMID:36514469 reported a Chinese patient who presented with slowly progressive upper limb weakness, predominantly affecting distal muscles and was identified with heterozygous variant p.Val256Met in CASQ1.

This gene has been associated with relevant phenotypes in OMIM (MIM #616231), but not in Gene2Phenotype.

Created: 3 May 2023, 11:05 a.m. | Last Modified: 3 May 2023, 11:05 a.m.

Panel Version: 4.15

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Myopathy, vacuolar, with CASQ1 aggregates, OMIM:616231

Publications

• 26136523
• 28895244
• 29039140
• 30258016
• 34908252
• 36514469

Green List (high evidence)

PMID: 26136523 - 3 unrelated families (10 patients) with a founder missense (p.Asp244Gly) with muscle weaknesses. All patients reported adult onset. 1 proband reported lower limb hypertrophy with normal EMG results. 6 patients had muscle biopsy, with minimal fibre size variation, and a few central nuclei. PMID: 30258016 - 12 families (22 patients), or which 21 had the recurring p.Asp244Gly mutation. Patients all had adult onset, elevated CK, with slowly progressive proximal weakness with quadriceps atrophy and scapular winging. Pelvic girdle weakness was reported in 4/22 patients. Very large number of individuals reported with same founder variant, consider promoting to Green. Italian rather than rare, isolated population.

Created: 29 Jun 2020, 10:39 a.m. | Last Modified: 29 Jun 2020, 10:41 a.m.

Panel Version: 2.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Myopathy, vacuolar, with CASQ1 aggregates, MIM#616231

Publications

• 26136523
• 30258016

Comment on list classification: Promoted from Red to Amber due to expert review, however only one missense variants seems to have been reported in this gene. Awaiting further clinical input for this to be Green.

Created: 28 Nov 2019, 5:16 p.m. | Last Modified: 28 Nov 2019, 5:16 p.m.

Panel Version: 1.161

Green List (high evidence)

new gene added Currently provided as part of our LGMD panel at HSS LGMD in Ncl.

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

Panel Version: 1.97

I don't know

New gene requested to be added to panel by Chiara Marini Bettolo (NUTH) on behalf of Yorkshire North East
Sources: Expert Review

Created: 21 Oct 2019, 11:02 a.m.

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

Phenotypes
Myopathy, vacuolar, with CASQ1 aggregates, 616231