Non-allelic homologous recombination leading to premature transcription termination in the ARSB gene as a novel cause of Mucopolysaccharidosis type VI

Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disorder associated with pathogenic variants in the ARSB gene. Herein, we present a novel type of ARSB mutations, which is an insertion of the LHFPL2 gene fragment derived from unequal non-allelic homologous recombination between these two genes. The 52 kb insertion, containing the LHPL2 exon 3, was identified in reverse complement orientation deep in the intron 4 of ARSB using whole genome sequencing. Subsequent RNA analysis determined its deleterious effect, which is premature transcription termination. Two mobile genetic elements of the L1 class with high sequence similarity were identified in both genes at the site of recombination and their close spatial proximity is suggested to favor structural rearrangements in this locus. The recombination was identified in compound heterozygous state with the nonsense variant c.966G>A (p.Trp322*) in patient with an early-onset form of MPS VI. Almost complete absence of the full-length ARSB mRNA isoform expression from both alleles correlates well with a severe phenotype of the patient. The results of our study expand mutational spectrum of the ARSB gene towards complex structural variants and novel molecular-genetic mechanisms.