Paediatric or syndromic cardiomyopathy

Gene: GLA

Green List (high evidence)

Comment on list classification: As there is sufficient evidence available for the association of GLA variants with hypertrophic cardiomyopathy as part of the Fabry disease phenotype, this gene can be promoted to green rating in the next GMS update.

Created: 6 Sep 2025, 5:29 p.m. | Last Modified: 6 Sep 2025, 5:29 p.m.

Panel Version: 7.77

There are >100 unrelated patients reported with Fabry disease (MIM #301500, OMIM accessed on 06 September 2025) and with GLA variants. Patients with Fabry disease present with
hypertrophic cardiomyopathy (left ventricular wall hypertrophy/ ventricular septal hypertrophy) as part of the phenotype. This gene is already green on R131 Hypertrophic cardiomyopathy panel (https://panelapp.genomicsengland.co.uk/panels/49/)

Below are some of the most recent published studies describing patients with GLA variants and Fabry disease/ hypertrophic cardiomyopathy:

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort. Two adult patients (one male and one female) with hypertrophic cardiomyopathy were identified with p.Asn215Ser missense variant in GLA gene. The male patient was a singleton sequenced and the female was sequenced together with another biological relative.

PMID:39620496 (2024) reported 12 patients with clinical and molecular diagnosis of Fabry disease treated at their institution and reviewed 40 additional Mexican Fabry disease patients previously reported in literature. 14 different variants in the GLA gene including a novel variant (c.122C>G) were identified in these patients. The most frequent manifestation in both sexes was acroparesthesias (37/52, 71.2%), followed by hypohidrosis or anhidrosis (25/52, 48.1%), heat intolerance (24/52, 46.2%), and proteinuria (22/52, 42.3%). Hypertrophic cardiomyopathy was reported in 10 patients (19.2%). Of the 12 new patients reported in this publication, 6 patients had left ventricular hypertrophy together with renal and/or neurological manifestations.

PMID:39995634 (2025) performed a causative gene analysis in patients with hypertrophic cardiomyopathy with mid-ventricular obstruction (HCM-MVO), and identified four female patients with different pathogenic variants of GLA, which were clinically confirmed as Fabry disease.

This gene is also present on the Eye, Skin and Cardiac panels of Gene2Phenotype resource with a 'definitive' rating.

Created: 6 Sep 2025, 5:21 p.m. | Last Modified: 6 Sep 2025, 5:21 p.m.

Panel Version: 7.74

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

Phenotypes
Fabry disease, OMIM:301500; Fabry disease, cardiac variant, OMIM:301500; Fabry disease, MONDO:0010526

Publications

• 39472908
• 39620496
• 39995634

I don't know

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.

Created: 2 Dec 2019, 3:58 p.m. | Last Modified: 2 Dec 2019, 3:58 p.m.

Panel Version: 0.16

Green List (high evidence)

This gene was included in Table 1 for a diagnostic test from the MetBioNet guideline - see publications field for URL to the guideline.

Created: 18 Apr 2019, 11:53 a.m.

Phenotypes
Fabry disease; Limb pain, angiokeratom; HCM is a late complication in adults, also found in female carriers; HCM

Publications

• National Metabolic Biochemistry Network Best Practice Guidelines Investigation of An Inherited Metabolic Cause of Cardiomyopathy, Authors: Ann Bowron, Simon Olpin (13 Jul 2012) http://www.metbio.net/metbioGuidelines.asp

I don't know

Fabry disease OMIM# 301500; Fabry disease, cardiac variant OMIM#301500

Created: 25 Mar 2019, 4:30 p.m.

Classic Fabry disease has a paediatric onset but cardiac symptoms develop usually in adulthood. Cardiac features are not the presenting features in early onset Fabry disease. There is cardiac variant disease.

Created: 25 Mar 2019, 4:27 p.m.

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

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