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Homozygous TFG gene variants expanding the mutational and clinical spectrum of hereditary spastic paraplegia 57 and a review of literature

Journal of Human Genetics volume 66, pages 973–981 (2021)Cite this article

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Abstract

In recent years, the tropomyosin-receptor kinase fused gene (TFG) has been linked to diverse hereditary neurodegenerative disorders, including a very rare complex hereditary spastic paraplegia, named spastic paraplegia type 57 (SPG57). Until now, four pathogenic homozygous variants of the TFG gene have been reported associated with SPG57. Two consanguineous Iranian families (1 and 2), the first one with two affected members and the second one with one, all with an early-onset progressive muscle weakness, spasticity, and several neurological symptoms were examined via the whole-exome sequencing. Two homozygous missense variants including c.41A>G (p.Lys14Arg) and c.316C>T (p.Arg106Cys) have been found in the related families. The candidate variants were confirmed by Sanger sequencing and found to co-segregate with the disease in families. The bioinformatics analysis showed the deleterious effects of these nucleotide changes and the variants were classified as pathogenic according to ACMG guidelines. A comparison of the clinical presentation of the patients harboring c.41A>G (p.Lys14Arg) with previously reported SPG57 revealed variability in the severity state and unreported clinical presentation, including, facial atrophy, nystagmus, hyperelastic skin, cryptorchidism, hirsutism, kyphoscoliosis, and pectus excavatum. The affected member of the second family carried a previously reported homozygous c.316C>T (p.Arg106Cys) variant and displayed a complex HSP including optic atrophy. Remarkable clinical differences were observed between the family 1 and 2 harboring the c.41A>G (p.Lys14Arg) and c.316C>T (p.Arg106Cys) variants, which could be attributed to the distinct affected domains (PB1 domains and coiled-coil domains), and therefore, SPG57 might have been representing phenotype vs. variant position correlation.

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Acknowledgements

We would like to express our special thanks to our patients, their families, the Isfahan University of Medical Science, and the medical genetics lab GENEAZMA for their collaboration.

Funding

The project was supported by deputies of research of Isfahan 361 University of Medical Sciences (394950).

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Authors and Affiliations

  1. Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

    Mehdi Khorrami, Mohammad Amin Tabatabaiefar, Erfan Khorram & Majid Kheirollahi

  2. Department of Pediatrics, School of Medicine, Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

    Omid Yaghini

  3. Department of Biology, Faculty of Science, Yazd University, Yazd, Iran

    Mojgan Rezaei

  4. Department of Biology, School of Sciences, The University of Isfahan, Isfahan, Iran

    Arash Hejazifar

  5. Department of Radiology, Isfahan University of Medical Sciences, Isfahan, Iran

    Maryam Riahinezhad

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  1. Mehdi Khorrami
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Contributions

MK: Contributed to data analysis, laboratory works, and writing the papers. MAT: Supervised the genetic analyses and critical revision of the article. EK: Contributed to paper writing and laboratory works. OY: Supervised the clinical evaluation. MR: Contributed to data collection and laboratory works. AH: Contributed to data analysis and interpretation. MR: Contributed to clinical evaluation. MK: Designed and supervised the study.

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Correspondence to Majid Kheirollahi.

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The authors declare no competing interests.

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The study was approved by the Ethical Committee of the Isfahan Medical University of Science (IR.MUI.MED.REC.1398.186).

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Khorrami, M., Tabatabaiefar, M.A., Khorram, E. et al. Homozygous TFG gene variants expanding the mutational and clinical spectrum of hereditary spastic paraplegia 57 and a review of literature. J Hum Genet 66, 973–981 (2021). https://doi.org/10.1038/s10038-021-00919-9

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