ATAD3A – Harel-Yoon Syndrome

Harel-Yoon syndrome is a neurodevelopmental disorder caused by pathogenic variants in the ATAD3A gene (HGNC:25567), manifesting with features such as developmental cataract (HP:0000519), hypotonia (HP:0001252), and global developmental delay (HP:0001263). Several independent case reports and multi‐patient studies have demonstrated that patients harbor compound heterozygous alterations, including both missense changes and copy number variations. In one representative case, a Chinese boy with refractory epilepsy was found to carry the missense variant c.251T>C (p.Thr84Met) (PMID:37031571), which, along with additional familial segregation data (PMID:38877820), supports the role of ATAD3A variants in disease pathogenesis.

Genetic evidence across diverse populations reinforces the association with Harel-Yoon syndrome. Multiple reports document recurrent variants—including the aforementioned c.251T>C (p.Thr84Met)—in patients with overlapping phenotypes ranging from refractory epilepsy to ocular abnormalities. Segregation analyses in extended families (with at least 19 affected relatives noted in the literature PMID:38877820) further substantiate the genetic contribution of ATAD3A.

Functional studies provide additional support for a pathogenic mechanism. Experimental models, including patient-derived induced pluripotent stem cells and Drosophila knockin-null systems, have demonstrated impaired mitochondrial function, aberrant ATPase activity, and disrupted mitochondrial dynamics (PMID:40246775; PMID:27640307). These findings align with the clinical phenotype of mitochondrial dysfunction observed in affected individuals.

The combined genetic and experimental evidence converges on a strong association between ATAD3A variants and Harel-Yoon syndrome. The recurrent identification of the missense variant c.251T>C (p.Thr84Met), along with copy number alterations and supportive segregation data, establishes ATAD3A as a critical gene in this disorder, inherited in an autosomal recessive fashion.

Key take‑home sentence: The robust correlation between diverse ATAD3A mutations and the clinical spectrum of Harel-Yoon syndrome underscores the clinical utility of incorporating ATAD3A sequencing in the diagnostic workup of patients with neurodevelopmental delay, hypotonia, and ocular abnormalities.

References

• Pediatric neurology • 2023 • Ketogenic Diet Attenuates Refractory Epilepsy of Harel-Yoon Syndrome With ATAD3A Variants: A Case Report and Review of Literature PMID:37031571
• Ophthalmic genetics • 2023 • Harel Yoon syndrome: a novel mutation in ATAD3A gene and expansion of the clinical spectrum PMID:36856321
• Heliyon • 2024 • Harel-Yoon syndrome caused by a novel variant in ATAD3A: A case report PMID:38173481
• American journal of medical genetics. Part A • 2024 • Expanding the phenotype of Harel-Yoon syndrome: A case report suggesting a genotype/phenotype correlation PMID:38877820
• Human cell • 2025 • Clinical characteristics and induced pluripotent stem cells (iPSCs) disease model of Harel-Yoon syndrome caused by compound heterozygous ATAD3A variants PMID:40246775
• American journal of human genetics • 2016 • Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes PMID:27640307

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