Paediatric or syndromic cardiomyopathy

Gene: ATAD3A

Green List (high evidence)

Appropriate for R135 panel due to recurrent duplication (PMID: 33575671) which can present as perinatal HCM (we have reported one case in our WGS cohort) Also for other variant types (see review below for PMIDs), HCM or other cardiomyopathy can be presenting feature (eg: PMID: 39472908

Created: 6 Jan 2026, 1:43 p.m. | Last Modified: 6 Jan 2026, 1:43 p.m.

Panel Version: 7.92

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
perinatal mitochondrial cardiac failure

Publications

• 33575671
• 39472908

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

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants in ATAD3A gene with syndromic cardiomyopathy.

Although the majority of the cases are reported with CNVs involving deletions or duplications of ATAD3 gene cluster (ATAD3A, ATAD3B & ATAD3C genes), there are also patients reported with small variants in monoallelic or biallelic states (as homozygous or as compound heterozygous with the CNV).

Hence, this gene can be promoted to green rating in the next GMS update.

Created: 2 Sep 2025, 12:45 p.m. | Last Modified: 2 Sep 2025, 12:45 p.m.

Panel Version: 7.70

Comment on phenotypes: OMIM phenotypes accessed on 02 September 2025.

Created: 2 Sep 2025, 11:34 a.m. | Last Modified: 2 Sep 2025, 11:34 a.m.

Panel Version: 7.69

PMID:27640307 (2016) reported the identification of the same recurrent de novo ATAD3A variant (c.1582C>T/ p.Arg528Trp) in five unrelated individuals. Their clinical presentations included global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy (HCM). HCM was identified in two of five patients. This study also reported two additional families with biallelic ATAD3A variants - one family with homozygous c.158C>T/ p.Thr53Ile variant and the unrelated newborn with biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. The newborn with the deletion variants had mild RVH with septal hypertrophy.

PMID:28549128 (2017) reported five patients from four unrelated families with fatal congenital pontocerebellar hypoplasia and with large biallelic deletions that generate chimeric ATAD3B/ATAD3A fusion genes. Progressive cardiac hypertrophy was reported in one of five patients.

PMID:31727539 (2019) reported the identification of a novel homozygous missense variant in ATAD3A gene (c.1217 T > G/ p.Leu406Arg) in four siblings from a consanguineous family presenting with fatal neonatal cerebellar hypoplasia, seizures, axial hypotonia, HCM, hepatomegaly, congenital cataract, and dysmorphic facies. HCM was reported in all four patients.

PMID:32004445 (2020) reported five unrelated neonates with a heterozygous 67-kb duplication at 1p36.33 creating an in-frame ATAD3A–ATAD3C fusion gene. They presented with a disorder characterised by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures. HCM and DCM were reported in three and two patients respectively.

PMID:33575671 (2021) reported the investigation of 17 patients from 16 unrelated families, where six different de novo duplications in the ATAD3 gene locus (ATAD3A–ATAD3C fusion duplications) were reported. They presented with lethal perinatal cardiomyopathy, persistent hyperlactacidemia, and frequently corneal clouding or cataracts and encephalopathy.

PMID:37095554 (2023) reported four patients from two families with compound heterozygous c.229C>G (p.Leu77Val) variant and 3-4 exon deletion in ATAD3A gene. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. Two patients from one of these two families were reported with mild HCM.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which two paediatric patients with unspecified cardiomyopathy were identified with de novo heterozygous duplication in ATAD3 gene cluster via reanalysis of data from trio genome sequencing.

Both monoallelic and biallelic variants in ATAD3A gene have been reported with relevant phenotypes in both OMIM (MIM #617183) and Gene2Phenotype (definitive rating for monoallelic and strong rating for biallelic on the DD panel). Records from both resources include hypertrophic cardiomyopathy as part of the phenotype. This gene is also green on the 'Cardiomyopathy_Paediatric' panel on PanelApp Australia.
Sources: Literature

Created: 2 Sep 2025, 11:33 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Harel-Yoon syndrome, OMIM:617183; Harel-Yoon syndrome, MONDO:0014958; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, MONDO:0032931

Publications

• 27640307
• 28549128
• 31727539
• 32004445
• 33575671
• 37095554