Precision Therapy for a Medically Actionable ATP1A3 Variant From a Genomic Medicine Program in an Underserved Population

Authors

Cara P Ford
Rebecca O Littlejohn
Ryan German
Blake Vuocolo
Jose Aceves
Liesbeth Vossaert
Nichole Owen
Michael Wangler
Carrie A Schmid

Publication Date

12-1-2023

Journal

Molecular Genetics and Metabolism

DOI

10.1002/mgg3.2272

PMID

37614148

PMCID

PMC10724509

PubMedCentral® Posted Date

8-23-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Male, Humans, Child, Hemiplegia, Mutation, Genomic Medicine, Vulnerable Populations, Mouth Mucosa, Sodium-Potassium-Exchanging ATPase, alternating hemiplegia of childhood, ATP1A3, genomics, health care equity, underserved population

Abstract

Background: Genomic medicine is revolutionizing the diagnosis of rare diseases, but the implementation has not benefited underrepresented populations to the same degree. Here, we report the case of a 7-year-old boy with hypotonia, global developmental delay, strabismus, seizures, and previously suspected mitochondrial myopathy. This proband comes from an underrepresented minority and was denied exome sequencing by his public insurance.

Methods: After informed consent was obtained, buccal cells from the proband were collected and whole exome sequencing was performed. Illumina Dragen and Emedgene software was used to analyze the data at Baylor Genetics. The variants were further intepreted according to ACMG guidelines and the patient's phenotype.

Results: Through whole-exome sequencing (WES) under the Community Texome project, he was found to have a heterozygous de novo pathogenic variant in the ATP1A3 gene located on chromosome 19q13.

Conclusion: In retrospect, his symptomatology matches the known medical conditions associated with the ATP1A3 gene namely Alternating Hemiplegia of Childhood 2 (AHC), a rare autosomal dominant disorder with an incidence of 1 in one million. His single nucleotide variant, (c.2401G>A, p.D801N), is predicted to be damaging. The specific amino acid change p.D801N has been previously reported in ClinVar along with the allelic variant p.D801Y and both are considered pathogenic. The identification of this variant altered medical management for this patient as he was started on a calcium antagonist and has reported no further hemiplegic episodes. This case illustrates the value of implementing genomic medicine for precision therapy in underserved populations.