Novel IDUA variant confirmed in MPS I as embryo screening yields healthy child

A novel missense variant in the IDUA gene, c.1379T>C (p.Leu460Pro), has been linked for the first time to mucopolysaccharidosis type I (MPS I), according to a study published in BMC Medical Genomics. The work also documents the successful use of preimplantation genetic testing for monogenic disorders (PGT-M) in a Chinese family, resulting in the birth of a child who remained free of MPS I manifestations through three years of follow-up.

MPS I is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the IDUA gene. These variants lead to deficient activity of the enzyme α-L-iduronidase, which in turn allows glycosaminoglycans to accumulate progressively in tissues. The study set out to determine the genetic basis of MPS I in a Chinese proband, to apply PGT-M to prevent transmission of the disease, and to validate the pathogenicity of the previously unreported variant.

To identify the causative mutations, the researchers used targeted gene panel sequencing followed by Sanger sequencing confirmation. This revealed two heterozygous IDUA variants in the proband: a previously reported nonsense variant, c.1855C>T (p.Arg619Ter), inherited on one allele, and the novel missense variant c.1379T>C (p.Leu460Pro) on the other. The combination of variants fit the autosomal recessive inheritance pattern expected for the disorder.

The pathogenicity of the new variant was evaluated according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). In silico analyses supported a deleterious effect of the p.Leu460Pro substitution, contributing to the classification of the variant as pathogenic. The authors state that, to their knowledge, this is the first report associating c.1379T>C with MPS I, expanding the known IDUA mutation spectrum.

With both parental variants identified, the family underwent PGT-M. The procedure used trophectoderm biopsy combined with SNP haplotyping to determine which embryos carried the pathogenic variants. This approach allowed selection of an embryo that carried neither the paternal c.1855C>T variant nor the maternal c.1379T>C variant.

Prenatal diagnosis by amniocentesis subsequently confirmed the absence of both pathogenic variants in the fetus. A healthy neonate was delivered, and follow-up over three years showed normal growth and neurodevelopment with no clinical manifestations of MPS I. The case therefore documents a complete chain from molecular diagnosis to reproductive outcome in a single pedigree.

Beyond the reproductive outcome, the identification of p.Leu460Pro as a disease-associated variant adds to the catalog of IDUA mutations relevant to genetic counseling. The report, published as a peer-reviewed accepted manuscript with a permanent DOI, is described by its authors as valuable evidence for counseling high-risk families, though it rests on a single pedigree and the variant’s classification followed ACMG criteria supported by computational rather than functional analyses.

Subject of Research: Validation of a novel IDUA variant in MPS I and preimplantation genetic testing in an affected family

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

Article References: Gao, S., Liao, J., Zhou, Y., Sun, F., & Ma, Y. (2026). Expansion of the IDUA mutation spectrum: pathogenic validation of c.1379T > C in MPS I and application of PGT-M in a Chinese pedigree. BMC Medical Genomics. https://doi.org/10.1186/s12920-026-02455-x

Image Credits: AI Generated

DOI: 10.1186/s12920-026-02455-x

Keywords: MPS I, IDUA, lysosomal storage disorder, PGT-M, preimplantation genetic testing, ACMG guidelines, SNP haplotyping, genetic counseling, mutation spectrum, prenatal diagnosis, Expansion, mutation