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A case of de novo splice site variant in SLC35A2 showing developmental delays, spastic paraplegia, and delayed myelination.

Abstract

BACKGROUND

Congenital disorders of glycosylation (CDGs) are genetic diseases caused by pathogenic variants of genes involved in protein or lipid glycosylation. De novo variants in the SLC35A2 gene, which encodes a UDP-galactose transporter, are responsible for CDGs with an X-linked dominant manner. Common symptoms related to SLC35A2 variants include epilepsy, psychomotor developmental delay, hypotonia, abnormal facial and skeletal features, and various magnetic resonance imaging (MRI) findings.

METHODS

Whole-exome sequencing was performed on the patient's DNA, and candidate variants were confirmed by Sanger sequencing. cDNA analysis was performed to assess the effect of the splice site variant using peripheral leukocytes. The X-chromosome inactivation pattern was studied using the human androgen receptor assay.

RESULTS

We identified a de novo splice site variant in SLC35A2 (NM_005660.2: c.274+1G>A) in a female patient who showed severe developmental delay, spastic paraplegia, mild cerebral atrophy, and delayed myelination on MRI, but no seizures. The variant led to an aberrant splicing resulting in an in-frame 33-bp insertion, which caused an 11-amino acid insertion in the presumptive cytoplasmic loop. X-inactivation pattern was random. Partial loss of galactose and sialic acid of the N-linked glycans of serum transferrin was observed.

CONCLUSION

This case would expand the phenotypic spectrum of SLC35A2-related disorders to delayed myelination with spasticity and no seizures.

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  • Authors+Show Affiliations

    ,

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

    ,

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

    ,

    Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata, Japan.

    ,

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

    ,

    Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.

    ,

    Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo, Japan.

    ,

    Department of Pediatrics and Pediatric Neurology, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Japan.

    ,

    Department of Pediatrics, Jichi Medical University, Tochigi, Japan.

    ,

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

    ,

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

    ,

    Department of Molecular Medicine, Osaka Women's and Children's Hospital, Osaka, Japan.

    ,

    Department of Molecular Medicine, Osaka Women's and Children's Hospital, Osaka, Japan. Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka, Japan.

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

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31231989

    Citation

    Miyamoto, Sachiko, et al. "A Case of De Novo Splice Site Variant in SLC35A2 Showing Developmental Delays, Spastic Paraplegia, and Delayed Myelination." Molecular Genetics & Genomic Medicine, 2019, pp. e814.
    Miyamoto S, Nakashima M, Ohashi T, et al. A case of de novo splice site variant in SLC35A2 showing developmental delays, spastic paraplegia, and delayed myelination. Mol Genet Genomic Med. 2019.
    Miyamoto, S., Nakashima, M., Ohashi, T., Hiraide, T., Kurosawa, K., Yamamoto, T., ... Saitsu, H. (2019). A case of de novo splice site variant in SLC35A2 showing developmental delays, spastic paraplegia, and delayed myelination. Molecular Genetics & Genomic Medicine, pp. e814. doi:10.1002/mgg3.814.
    Miyamoto S, et al. A Case of De Novo Splice Site Variant in SLC35A2 Showing Developmental Delays, Spastic Paraplegia, and Delayed Myelination. Mol Genet Genomic Med. 2019 Jun 23;e814. PubMed PMID: 31231989.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A case of de novo splice site variant in SLC35A2 showing developmental delays, spastic paraplegia, and delayed myelination. AU - Miyamoto,Sachiko, AU - Nakashima,Mitsuko, AU - Ohashi,Tsukasa, AU - Hiraide,Takuya, AU - Kurosawa,Kenji, AU - Yamamoto,Toshiyuki, AU - Takanashi,Junichi, AU - Osaka,Hitoshi, AU - Inoue,Ken, AU - Miyazaki,Takehiro, AU - Wada,Yoshinao, AU - Okamoto,Nobuhiko, AU - Saitsu,Hirotomo, Y1 - 2019/06/23/ PY - 2019/02/25/received PY - 2019/05/30/revised PY - 2019/05/31/accepted PY - 2019/6/25/entrez KW - SLC35A2 KW - congenital disorders of glycosylation KW - delayed myelination KW - spastic paraplegia KW - splice site variant SP - e814 EP - e814 JF - Molecular genetics & genomic medicine JO - Mol Genet Genomic Med N2 - BACKGROUND: Congenital disorders of glycosylation (CDGs) are genetic diseases caused by pathogenic variants of genes involved in protein or lipid glycosylation. De novo variants in the SLC35A2 gene, which encodes a UDP-galactose transporter, are responsible for CDGs with an X-linked dominant manner. Common symptoms related to SLC35A2 variants include epilepsy, psychomotor developmental delay, hypotonia, abnormal facial and skeletal features, and various magnetic resonance imaging (MRI) findings. METHODS: Whole-exome sequencing was performed on the patient's DNA, and candidate variants were confirmed by Sanger sequencing. cDNA analysis was performed to assess the effect of the splice site variant using peripheral leukocytes. The X-chromosome inactivation pattern was studied using the human androgen receptor assay. RESULTS: We identified a de novo splice site variant in SLC35A2 (NM_005660.2: c.274+1G>A) in a female patient who showed severe developmental delay, spastic paraplegia, mild cerebral atrophy, and delayed myelination on MRI, but no seizures. The variant led to an aberrant splicing resulting in an in-frame 33-bp insertion, which caused an 11-amino acid insertion in the presumptive cytoplasmic loop. X-inactivation pattern was random. Partial loss of galactose and sialic acid of the N-linked glycans of serum transferrin was observed. CONCLUSION: This case would expand the phenotypic spectrum of SLC35A2-related disorders to delayed myelination with spasticity and no seizures. SN - 2324-9269 UR - https://www.unboundmedicine.com/medline/citation/31231989/A_case_of_de_novo_splice_site_variant_in_SLC35A2_showing_developmental_delays,_spastic_paraplegia,_and_delayed_myelination L2 - https://doi.org/10.1002/mgg3.814 DB - PRIME DP - Unbound Medicine ER -