New Term Request: Harel-Yoon syndrome

[vjenkinsFB]

I'd like to request a term for Harel-Yoon syndrome. This disease is associated w/a gene ATAD3A (https://omim.org/entry/612316) that is also associated with pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal (PHRINL, https://omim.org/entry/618810). These diseases are distinguished by phenotype, namely the lethality of the second one, which also doesn’t have a DO term. I’m not requesting that one, but it might be helpful to do both so they can reference each other.

OMIM: https://omim.org/entry/617183

Potential definition: Harel-Yoon syndrome has_material_basis_in heterozygous mutation or homozygous mutation in the ATAD3A gene on chromosome 1p36.

Potential parent term: syndrome

Synonyms: HAYOS, ocular anomalies-axonal neuropathy-developmental delay syndrome

ClinVar search term: ATAD3A[gene] AND ((("clinsig pathogenic"[Properties] OR "clinsig pathogenic low penetrance"[Properties] OR "clinsig established risk allele"[Properties]) OR ("clinsig likely pathogenic"[Properties] OR "clinsig likely pathogenic low penetrance"[Properties] OR "clinsig likely risk allele"[Properties]) OR ("clinsig has conflicts"[Properties]) OR ("clinsig vus"[Properties] OR "clinsig uncertain risk allele"[Properties])) AND (1[VARLEN] : 1000[VARLEN] AND "single gene"[Properties]))

MedGen page(s) pointed to by the above: Harel-Yoon syndrome https://www.ncbi.nlm.nih.gov/medgen/C4310677/, pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal https://www.ncbi.nlm.nih.gov/medgen/C5394137/

MalaCards page: https://www.malacards.org/card/harel_yoon_syndrome

Orpha.net: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=496790 (source of the synonym)

HGNC entry for gene: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:25567

Citations other than those in the OMIM entry:

• https://pubmed.ncbi.nlm.nih.gov/33845882/ Yap ZY, Park YH, Wortmann SB, et al. Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes. Genome Med. 2021;13(1):55. Published 2021 Apr 12. doi:10.1186/s13073-021-00873-3
• https://pubmed.ncbi.nlm.nih.gov/35012852/ Qi R, Li R, Yang W, Sang Y. Harel-Yoon syndrome caused by the c.368G>A variant in the ATAD3A gene: A case report. Asian J Surg. 2022;45(3):914-916. doi:10.1016/j.asjsur.2021.12.059Qi R, Li R, Yang W, Sang Y. Harel-Yoon syndrome caused by the c.368G>A variant in the ATAD3A gene: A case report. Asian J Surg. 2022;45(3):914-916. doi:10.1016/j.asjsur.2021.12.059
• https://pubmed.ncbi.nlm.nih.gov/36856321/ Tawfik CA, Zaitoun R, Farag AA. Harel Yoon syndrome: a novel mutation in ATAD3A gene and expansion of the clinical spectrum [published online ahead of print, 2023 Mar 1]. Ophthalmic Genet. 2023;1-8. doi:10.1080/13816810.2023.2183223
• https://pubmed.ncbi.nlm.nih.gov/32607449/ Hanes I, McMillan HJ, Ito Y, et al. A splice variant in ATAD3A expands the clinical and genetic spectrum of Harel-Yoon syndrome. Neurol Genet. 2020;6(4):e452. Published 2020 Jun 3. doi:10.1212/NXG.0000000000000452

Other links: patient self-advocacy site https://www.atad3a.com/

FlyBase paper(s) to curate with this term: FBrf0248703, FBrf0233629

My contact info: vjenkins@morgan.harvard.edu (FlyBase), 0000-0002-1567-7626. Thank you!

[csbjohnson]

Thank you very much for your request @vjenkinsFB. We'll review the detailed information you provided on Harel-Yoon syndrome , get back to you soon and update the DO for the next release.

Thank you!

[allenbaron]

Additional ATAD3-related disease: 'chromosome 1p36.33 duplication syndrome' (OMIM:618815).

Additional publication:

• https://pubmed.ncbi.nlm.nih.gov/37095554/ Skopkova M, Stufkova H, Rambani V, et al. ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability. Orphanet J Rare Dis. 2023;18(1):92. Published 2023 Apr 24. doi:10.1186/s13023-023-02689-3

This one attempts to summarize the genotype-phenotype relationships and has been shared with OMIM.

[allenbaron]

These diseases are almost complete, just awaiting minor review by @lschriml for a second decision. The distinction between PHRINL (OMIM:618810), Harel-Yoon (OMIM:617183, and chromosome 1p36.33 deletion syndromes is a bit hazy at the moment.

From what I can tell OMIM has classified these based on disease outcome and mutation type:

• Point mutations that don’t result in death = Harel-Yoon (AD/AR)
• Point mutations that result in neonatal death = PHRINL (AR)
• Biallelic deletion = chromosome 1p36.33 deletion syndrome (but lumped in with PHRINL and called PHRINL in text) (AR)

Whereas in a recent review Skopkova, et al chose to classify them primarily by inheritance:

• Autosomal recessive (includes all mutation types: deletion, missense, rearrangement) = PHRINL
  • Gave PHRINL degrees based on presumed variant severity
• de novo (AD) point mutation = Harel-Yoon
• Autosomal dominant inherited point mutation = hereditary spastic paraplegia

Skopkova M, Stufkova H, Rambani V, et al. ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability. Orphanet J Rare Dis. 2023;18(1):92. Published 2023 Apr 24. doi:10.1186/s13023-023-02689-3

A particularly confusing example described by Desai (patient S5) with a deletion/rearrangement was summarized by OMIM in the PHRINL article at https://omim.org/entry/618810#genotypePhenotypeCorrelations with text suggesting the phenotype is more consistent with Harel-Yoon syndrome.

[vjenkinsFB]

I don't doubt that these things get complicated! Thanks so much for making these terms.

[allenbaron]

The literature for these diseases is very inconsistent with regard to nomenclature and distinguishing Harel-Yoon and PHRINL syndromes, so we've decided to wait for OMIM to also review their records prior to creating them. Apologies for the delay. Thanks for understanding!

chromosome 1p36.33 duplication syndrome is more clear cut and will be added in the next release.

[lschriml]

I have added the two OMIM Syndrome terms.