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A novel heterozygous TMEM63A variant in a familial case with early onset nystagmus, severe hypomyelination, and a favorable adult prognosis

Journal of Human Genetics (2024)Cite this article

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Abstract

Heterozygous transmembrane protein 63A (TMEM63A) variants cause transient infantile hypomyelinating leukodystrophy-19, which features remarkable natural resolution of clinical and imaging findings during childhood. Previous reports have mainly described de novo variants lacking detailed familial cases. Herein, we describe the clinical course of familial cases with a TMEM63A variant. A 5-month-old girl presented with nystagmus, global hypotonia, and difficulty swallowing since birth. Brain magnetic resonance imaging at 1.5 and 5 months revealed diffuse hypomyelination. Her mother, maternal aunt, and grandfather had nystagmus and motor developmental delays in infancy, which resolved spontaneously during childhood. Compared with these cases, the proband’s motor developmental delay was profound, and she was the only one with feeding difficulties, necessitating nasogastric tube feeding. Genetic testing revealed a heterozygous TMEM63A variant (NM_014698.3:c.1658G>A, p.(Gly553Asp)) in the proband and her family. This is the first three-generation familial report of a TMEM63A variant that provides insight into its history and heterogeneity.

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Data availability

The nucleotide sequence date reported are available in the ClinVar database under the accession number SCV004812254.

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Acknowledgements

The authors thank the patient and her family for their cooperation and consent for the publication of this report. We would like to thank Editage (www.editage.jp) for English language editing.

Funding

This study was funded in part by grants from the Japan Agency for Medical Research and Development (AMED) under grant number JP23ek0109637 to KI and HS, the Ministry of Health, Labour and Welfare under grant number JPMH21FC1015 to KI and HS, and the Intramural Research Grant (3-6 and 6-6) for Neurological and Psychiatric Disorders of the National Center of Neurology and Psychiatry to YSM. The funding organizations had no role in the design or conduct of the study. The funding organization had no role in the collection, management, analysis, interpretation of data, preparation, review, or approval of the manuscript.

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Authors and Affiliations

  1. Department of Child Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan

    Shota Yoneno, Kaoru Yamamoto, Yuko Shimizu-Motohashi & Hirofumi Komaki

  2. Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

    Kenshiro Tabata & Ken Inoue

  3. Department of Neonatology, Toho University Omori Medical Center, Tokyo, Japan

    Ayaka Tomita

  4. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Taiju Hayashi & Hirotomo Saitsu

  5. Department of Radiology, National Center of Neurology and Psychiatry, Tokyo, Japan

    Hiroyuki Maki & Noriko Sato

  6. Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan

    Hirofumi Komaki

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  1. Shota Yoneno
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  2. Kaoru Yamamoto
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  10. Hirotomo Saitsu
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Contributions

SY, KY, YSM, and KI analyzed the data and wrote the manuscript. SY, KY, KT, AT, HM, and NS examined and evaluated the case. TH and HS performed multiple panel testing. KI and HK supervised the study.

Corresponding author

Correspondence to Kaoru Yamamoto.

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The authors declare no competing interests.

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Yoneno, S., Yamamoto, K., Tabata, K. et al. A novel heterozygous TMEM63A variant in a familial case with early onset nystagmus, severe hypomyelination, and a favorable adult prognosis. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01268-z

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  • DOI: https://doi.org/10.1038/s10038-024-01268-z

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