"Missing mutations" in MPS I: Identification of two novel copy number variations by an IDUA-specific in house MLPA...

Area of Science:

• Genetics
• Biochemistry
• Rare Diseases

Background:

• Mucopolysaccharidosis type I (MPS I) is a rare, inherited lysosomal storage disorder.
• It results from deficient alpha-L-iduronidase (IDUA) enzyme activity due to IDUA gene variants.
• Some MPS I patients present with only one detectable mutated IDUA allele.

Purpose of the Study:

• To develop and apply an IDUA-specific multiplex ligation-dependent probe amplification (MLPA) assay.
• To detect copy number variations (CNVs) in the IDUA gene that are often missed by standard sequencing methods.
• To improve the diagnosis of MPS I by identifying underdiagnosed genetic causes.

Main Methods:

• Re-analysis of five MPS I patient samples with single heterozygous IDUA mutations.
• Utilized an in-house developed IDUA-specific multiplex ligation-dependent probe amplification (MLPA) assay.
• Sequencing methods were complemented by MLPA to detect CNVs.

Main Results:

• A novel splice site variant (c.973-7C>G) was identified.
• Two novel copy number variations (CNVs) in the IDUA gene were detected: a large deletion and a large duplication.
• These findings add to the previously reported pathogenic IDUA CNVs, bringing the total to four.

Conclusions:

• The IDUA-specific MLPA assay is effective in detecting CNVs in MPS I patients.
• CNVs in the IDUA gene are an underdiagnosed cause of MPS I.
• This study expands the spectrum of known pathogenic variants in the IDUA gene, aiding in comprehensive MPS I diagnosis.