[Mutation analysis for a methylmalonic acidemia pedigree without proband by high-throughput sequencing]

Area of Science:

• Genetics
• Genomic Medicine
• Molecular Diagnostics

Background:

• Methylmalonic acidemia is an autosomal recessive metabolic disorder.
• Genetic diagnosis is crucial for affected pedigrees, especially for prenatal screening.
• Identifying carriers is essential for reproductive planning in at-risk families.

Observation:

• High-throughput sequencing (HTS) was employed to screen 14 genes in parents of a child with methylmalonic acidemia.
• The study aimed to detect potential mutations in a pedigree lacking an affected proband for direct testing.
• Carrier status was assessed using HTS followed by Sanger sequencing validation.

Findings:

• The husband was identified as a heterozygous carrier for a MUT gene mutation (Exon 3: c.729_730insTT; p.Asp244Leufs*39).
• The wife was also identified as a heterozygous carrier for a different MUT gene mutation (Exon 5: c.914T>C; p.Leu305Ser).
• Prenatal testing of amniotic fluid revealed the fetus carried neither identified mutation, and the neonate showed no signs of methylmalonic acidemia.

Implications:

• HTS offers a sensitive, single-test approach for screening multiple genes.
• Carrier testing via HTS provides an alternative diagnostic strategy for autosomal recessive diseases when a proband is unavailable.
• Caution is advised when utilizing HTS for carrier screening in prenatal diagnostic settings.