Expansion of the IDUA mutation spectrum: pathogenic validation of c.1379T > C in MPS I and application of PGT-M in a Chinese pedigree

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the IDUA gene, leading to deficient α-L-iduronidase activity and progressive glycosaminoglycan accumulation. This study aimed to determine the genetic basis of MPS I in a Chinese proband, apply preimplantation genetic testing for monogenic disorders (PGT-M) to prevent disease transmission, and validate the pathogenicity of a novel IDUA variant. Targeted gene panel sequencing followed by Sanger confirmation identified two heterozygous IDUA variants: a previously reported nonsense variant (c.1855C > T, p.Arg619Ter) and a novel missense variant (c.1379T > C, p.Leu460Pro). The pathogenicity of the novel variant was evaluated according to the American College of Medical Genetics and Genomics (ACMG) guidelines, with in silico analyses supporting a deleterious effect. PGT-M was subsequently performed using trophectoderm biopsy and SNP haplotyping to select embryos without pathogenic variants. PGT-M enabled the selection of an embryo that carried neither the paternal IDUA c.1855C > T variant nor the maternal IDUA c.1379T > C variant. Prenatal diagnosis by amniocentesis confirmed the absence of pathogenic variants, and a healthy neonate was delivered. Follow-up over three years showed normal growth and neurodevelopment, with no clinical manifestations of MPS I. To our knowledge, this is the first report associating c.1379T > C (p.Leu460Pro) with MPS I, thereby expanding the IDUA mutation spectrum. Moreover, the successful application of PGT-M in this family highlights a replicable strategy for preventing transmission of MPS I and provides valuable evidence for genetic counseling in high-risk pedigrees.