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Two novel cases of biallelic SMPD4 variants with brain structural abnormalities

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Abstract

Sphingomyelin phosphodiesterase 4 (SMPD4) encodes a member of the Mg2+-dependent, neutral sphingomyelinase family that catalyzes the hydrolysis of the phosphodiester bond of sphingomyelin to form phosphorylcholine and ceramide. Recent studies have revealed that biallelic loss-of-function variants of SMPD4 cause syndromic neurodevelopmental disorders characterized by microcephaly, congenital arthrogryposis, and structural brain anomalies. In this study, three novel loss-of-function SMPD4 variants were identified using exome sequencing (ES) in two independent patients with developmental delays, microcephaly, seizures, and brain structural abnormalities. Patient 1 had a homozygous c.740_741del, p.(Val247Glufs*21) variant and showed profound intellectual disability, hepatomegaly, a simplified gyral pattern, and a thin corpus callosum without congenital dysmorphic features. Patient 2 had a compound heterozygous nonsense c.2124_2125del, p.(Phe709*) variant and splice site c.1188+2dup variant. RNA analysis revealed that the c.1188+2dup variant caused exon 13 skipping, leading to a frameshift (p.Ala406Ser*6). In vitro transcription analysis using minigene system suggested that mRNA transcribed from mutant allele may be degraded by nonsense-mediated mRNA decay system. He exhibited diverse manifestations, including growth defects, muscle hypotonia, respiratory distress, arthrogryposis, insulin-dependent diabetes mellitus, sensorineural hearing loss, facial dysmorphism, and various brain abnormalities, including cerebral atrophy, hypomyelination, and cerebellar hypoplasia. Here, we review previous literatures and discuss the phenotypic diversity of SMPD4-related disorders.

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Data Availability

The exome sequencing data of this study is not publicly available.

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Acknowledgements

We would like to thank the patient’s family for participating in this work.

Funding

This study was funded by the Japan Society for the Promotion of Science, KAKENHI (Grant number JP 20H03641 and 23H02875, JP20K08236 and JP21K06819), the Japan Agency for Medical Research and Development (AMED) (JP23ek0109549 and 23ek01099674, and 23ek0109637), the Takeda Science Foundation, and HUSM Grant-in-Aid from Hamamatsu University School of Medicine.

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Authors and Affiliations

  1. Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan

    Shintaro Aoki, Kazuki Watanabe, Mitsuko Nakashima & Hirotomo Saitsu

  2. Advanced Research Facilities & Services, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Shintaro Aoki

  3. Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan

    Mitsuhiro Kato

  4. Department of Pediatrics, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Yukihiko Konishi

  5. Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan

    Kazuo Kubota

  6. Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan

    Kazuo Kubota

  7. Department of Pediatrics, Gifu Prefectural General Medical Center, Gifu, Japan

    Emiko Kobayashi

Authors
  1. Shintaro Aoki
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  7. Mitsuko Nakashima
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  8. Hirotomo Saitsu
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Contributions

HS and MK contributed to the conception and design of the study. Material preparation, the acquisition, and analysis of ES data were performed by SA, KW, and MN. Medical examinations were carried out by YK, KK, and EK. SA, MK, MN, and HS contributed to the drafting of the text and preparing the figures. All authors revised and commented on the manuscript.

Corresponding authors

Correspondence to Mitsuko Nakashima or Hirotomo Saitsu.

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Ethics approval and consent to participate

Experimental protocols were approved by the Institutional Review Board of Hamamatsu University School of Medicine and Showa University Faculty of Medicine. Written informed consent was obtained from all participating families.

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The authors declare no competing interests.

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Aoki, S., Watanabe, K., Kato, M. et al. Two novel cases of biallelic SMPD4 variants with brain structural abnormalities. Neurogenetics 25, 3–11 (2024). https://doi.org/10.1007/s10048-023-00737-5

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  • DOI: https://doi.org/10.1007/s10048-023-00737-5

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