Paediatric or syndromic cardiomyopathy

Gene: AIFM1

Green List (high evidence)

Comment on list classification: There are >20 unrelated patients reported with hemizygous AIFM1 variants and with Combined oxidative phosphorylation deficiency 6 (MIM #300816). However, the disease has a variable presentation and cardiomyopathy was reported in four unrelated patients. As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.

Created: 25 Aug 2025, 6:20 p.m. | Last Modified: 25 Aug 2025, 6:20 p.m.

Panel Version: 7.20

Comment on phenotypes: OMIM phenotype accessed on 25 August 2025.

Created: 25 Aug 2025, 6:14 p.m. | Last Modified: 25 Aug 2025, 6:14 p.m.

Panel Version: 7.19

PMID:22019070 (2011) reported three siblings of Palestinian descent with early prenatal verntriculomegaly, of which two brothers were investigated further. The two brothers presented with infantile encephalomyopathy. One of them died at the age of 4 years due to cardiac failure secondary to aspiration pneumonia, and the other died at 3 months of age because of hypertrophic cardiomyopathy and aspiration pneumonia. Using linkage analysis in the family, followed by whole exome sequencing, a pathogenic variant in the AIFM1 gene was identified in patient B (c.923G > A/ p.Gly308Glu), which segregated with the disease state and was absent in 86 anonymous controls.

PMID:28967629 (2018) reported two unrelated male patients with AIFM1 variants and they displayed distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. Cardiomyopathy was only reported in patient 2, who also displayed severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, and hyporeflexia. The c.422C > T (p.Thr141Ile) hemizygous variant was identified in this patient via WES and validated by Sanger sequencing and was confirmed de novo.

PMID:34117073 (2021) reported three affected males (proband, brother and maternal uncle) exhibiting severe multisystem pathology, metabolic acidosis, and early demise. Biventricular hypertrophy was observed via foetal heart echocardiogram in the proband, and by limited autopsy in the maternal uncle. A missense hemizygous AIFM1 variant (c.506C > T/ p.Pro169Leu) was identified in the proband and sibling and this variant is absent in reference population databases, as discussed in this publication.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient was identified with hemizygous variant in AIFM1 gene (c.603_605del/ p.Arg201del?).

This gene is associated with Combined oxidative phosphorylation deficiency 6 (MIM #300816) in OMIM, which includes hypertrophic cardiomyopathy as one of the variable clinical presentations.
Sources: Literature

Created: 25 Aug 2025, 6:09 p.m.

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

Phenotypes
Combined oxidative phosphorylation deficiency 6, OMIM:300816; severe X-linked mitochondrial encephalomyopathy, MONDO:0010437

Publications

• 22019070
• 28967629
• 34117073
• 39472908