Paediatric or syndromic cardiomyopathy

Gene: FLII

Green List (high evidence)

Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available (three unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS update.

Created: 15 Aug 2025, 4:52 p.m. | Last Modified: 15 Aug 2025, 4:52 p.m.

Panel Version: 7.15

PMID:32870709 (2020) reported a large cohort of 205 unrelated patients with various forms of childhood-onset cardiomyopathy (CM), in which two unrelated patients of Saudi Arabian descent with infantile-onset dilated CM were identified with homozygous missense variants (p.Leu674Val & p.Arg1240Cys).

PMID:37561591 (2023) identified biallelic variants in FLII gene in three unrelated families with idiopathic, early-onset dilated CM of which two patients were the ones that were already reported in PMID:32870709. The third patient was a girl of Dutch descent that had onset of CM at around 2 months of age. This patient was identified with compound heterozygous variants (p.Gln454Ter & p.Arg1168Trp).

Introduction of patient-specific FLII variants into the zebrafish genome using CRISPR/Cas9 genome editing resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in the patients. In addition, functional studies also provided insights into the function of Flii during ventricular chamber morphogenesis that involves myocardial cell adhesion and myofibril organisation.

This gene has been associated with dilated CM phenotype in OMIM (MIM #620635).

Created: 15 Aug 2025, 4:49 p.m. | Last Modified: 15 Aug 2025, 6:44 p.m.

Panel Version: 7.15

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cardiomyopathy, dilated, 2J, OMIM:620635

Publications

• 32870709
• 37561591

Green List (high evidence)

Additional families described in PMID: 37561591. Enough for the green rating

Created: 11 Feb 2025, 11:44 a.m. | Last Modified: 11 Feb 2025, 11:44 a.m.

Panel Version: 6.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• PMID: 37561591

After NHSGenomic Medicine Service consideration, the rating of this gene has not been changed.

Created: 3 Mar 2022, 1:12 p.m. | Last Modified: 3 Mar 2022, 1:12 p.m.

Panel Version: 1.65

Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.

Created: 16 Apr 2021, 8:50 a.m. | Last Modified: 16 Apr 2021, 8:50 a.m.

Panel Version: 1.30

Green List (high evidence)

Two unrelated families reported with homozygous missense variants in PMID 32870709.

Geng (2021): Shown to affect sarcomere size in Drosophila model. FliI knockdown resulted in disorganised myofibrils and increase filamentous actin.
Campbell (2002): Hom mice - lethal, het - normal. K/O mouse model of related genes have cytoskeletal actin alterations. No survivors to observed cardiac phenotypes.

We are aware of a third family ascertained through our laboratory.
Sources: Literature

Created: 15 Apr 2021, 11 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Dilated cardiomyopathy

Publications

• 32870709