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.

近年来，原肌球蛋白受体激酶融合基因 ( TFG ) 与多种遗传性神经退行性疾病有关，包括一种非常罕见的复杂遗传性痉挛性截瘫，称为痉挛性截瘫 57 型 (SPG57)。到目前为止，TFG的四种致病性纯合变体据报道，该基因与 SPG57 相关。通过全外显子组测序检查了两个近亲伊朗家庭（1 和 2），第一个有两个受影响的成员，第二个有一个，都具有早发性进行性肌肉无力、痉挛和几种神经系统症状。在相关家族中发现了两个纯合错义变体，包括 c.41A>G (p.Lys14Arg) 和 c.316C>T (p.Arg106Cys)。候选变体通过 Sanger 测序得到证实，并发现与家族中的疾病共同分离。生物信息学分析显示了这些核苷酸变化的有害影响，根据 ACMG 指南，这些变异被归类为致病性变异。c.41A>G 患者临床表现的比较 (p. Lys14Arg) 与先前报道的 SPG57 揭示了严重状态的变异性和未报告的临床表现，包括面部萎缩、眼球震颤、皮肤过度弹性、隐睾、多毛症、脊柱后侧凸和漏斗胸。第二个家族的受影响成员携带先前报道的纯合 c.316C>T (p.Arg106Cys) 变体，并表现出复杂的 HSP，包括视神经萎缩。在具有 c.41A>G (p.Lys14Arg) 和 c.316C>T (p.Arg106Cys) 变体的家族 1 和 2 之间观察到显着的临床差异，这可归因于不同的受影响域（PB1 域和卷曲-coil 域），因此，SPG57 可能代表了表型与变体位置相关性。眼球震颤、皮肤超弹性、隐睾症、多毛症、脊柱后凸和漏斗胸。第二个家族的受影响成员携带先前报道的纯合 c.316C>T (p.Arg106Cys) 变体，并表现出复杂的 HSP，包括视神经萎缩。在具有 c.41A>G (p.Lys14Arg) 和 c.316C>T (p.Arg106Cys) 变体的家族 1 和 2 之间观察到显着的临床差异，这可归因于不同的受影响域（PB1 域和卷曲-coil 域），因此，SPG57 可能代表了表型与变体位置相关性。眼球震颤、皮肤超弹性、隐睾症、多毛症、脊柱后凸和漏斗胸。第二个家族的受影响成员携带先前报道的纯合 c.316C>T (p.Arg106Cys) 变体，并表现出复杂的 HSP，包括视神经萎缩。在具有 c.41A>G (p.Lys14Arg) 和 c.316C>T (p.Arg106Cys) 变体的家族 1 和 2 之间观察到显着的临床差异，这可归因于不同的受影响域（PB1 域和卷曲-coil 域），因此，SPG57 可能代表了表型与变体位置相关性。Arg106Cys) 变体并表现出复杂的 HSP，包括视神经萎缩。在具有 c.41A>G (p.Lys14Arg) 和 c.316C>T (p.Arg106Cys) 变体的家族 1 和 2 之间观察到显着的临床差异，这可归因于不同的受影响域（PB1 域和卷曲-coil 域），因此，SPG57 可能代表了表型与变体位置相关性。Arg106Cys) 变体并表现出复杂的 HSP，包括视神经萎缩。在具有 c.41A>G (p.Lys14Arg) 和 c.316C>T (p.Arg106Cys) 变体的家族 1 和 2 之间观察到显着的临床差异，这可归因于不同的受影响域（PB1 域和卷曲-coil 域），因此，SPG57 可能代表了表型与变体位置相关性。