Case report: A novel FARS2 deletion and a missense variant in a child with complicated, rapidly progressive spastic paraplegia

Abstract

Defects in FARS2 are associated with either epileptic phenotypes or a spastic paraplegia subtype known as SPG77. Here, we describe an 8-year-old patient with severe and complicated spastic paraplegia, carrying a missense variant (p.Pro361Leu) and a novel intragenic deletion in FARS2. Of note, the disease is unexpectedly progressing rapidly and in a biphasic way differently from the previously reported cases. Our study provides the first detailed molecular characterization of a FARS2 deletion and its underlying molecular mechanism, and demonstrates the need for combining different tools to improve the diagnostic rate.

Keywords: FARS2; SPG77; complicated spastic paraplegia; deletion; severe.

FIGURE 1

Schematic view and location of the FARS2 variants reported so far. The variants found in our patient are indicated in red, those found either in epileptic or spastic patients are underlined, and those found only in epileptic patients are indicated in black, while the variants associated only with spastic paraplegia are indicated in blue. To date, 41 pathogenic FARS2 variants have been found to be spread throughout the gene, including missense, non-sense, and splice-site variants, and deletions.

FIGURE 2

Timeline with relevant episodes in the case report presented.

FIGURE 3

(A) On the left, the family pedigree with the proband is indicated by an arrow and a black square. The non-affected individuals are indicated by unfilled symbols. On the right, electropherogram of the FARS2 p.Pro361Leu maternal variant found in the patient was compared to the wild-type sequence (wt). (B) Schematic view of FARS2 at the genomic level with an indication of breakpoint locations, deleted exons in light green, and hypotheses of the underlying genomic event (non-homologous end joining, NHEJ). gDNA electrophoresis of the junction fragment and the schematic view of the gDNA resulting from the deletion are shown here. In the following figure, we see electropherogram of the sequence generated from the deletion, which spans from intron 1 to 4 of FARS2. (C) On the left, we observe the cDNA electrophoresis of the wild-type sequence and the fragment generated by the paternal intragenic deletion (del). On the right, we observe the schematic view of FARS2 at the cDNA level with the indication of the deleted exons in light green and representation of the cDNA resulting from the deletion. In the following figure, we see electropherograms of the 925 nucleotide deletion that lead to the loss of exons 2–3–4, including the canonical starting codon in exon 2. An ATG, located 56 nucleotides downstream of the breakpoint, might generate a putative protein with 131 residues instead of the canonical 451. This putative protein product (if any) is likely inactive because it lacks the catalytic functional domain, while it retains the FARS2 linker region and the anticodon-binding domain as shown here.