A homozygous double mutation in SMN1: a complicated genetic diagnosis of SMA

Area of Science:

• Genetics
• Molecular Biology
• Pediatric Neurology

Background:

• Spinal muscular atrophy (SMA) is a frequent autosomal recessive disorder causing infant mortality.
• Standard diagnosis relies on SMN1 gene copy number determination.
• A subset of SMA patients (3-5%) harbor pathogenic SMN1 mutations beyond simple copy number variations.

Purpose of the Study:

• To report a complex case of SMA with compound heterozygous SMN1 mutations.
• To introduce a novel diagnostic approach for improved SMA diagnosis.
• To emphasize the need for advanced genetic testing in specific SMA cases.

Main Methods:

• Case report of an SMA patient with homozygous cis-acting SMN1 mutations.
• Development and application of a novel diagnostic assay.
• Utilizing capillary electrophoresis for precise mutant allele copy number determination.

Main Results:

• Identified a patient homozygous for two distinct SMN1 mutations (c.48_55dupGGATTCCG and c.662C>T) in cis.
• The patient's consanguineous parents were heterozygous carriers of these compound mutations.
• The novel assay and capillary electrophoresis provided accurate diagnosis, overcoming limitations of standard copy number analysis.

Conclusions:

• SMN1 mutations in SMA can be more complex than simple copy number changes.
• Advanced molecular diagnostic techniques are crucial for accurate SMA diagnosis in intricate genetic scenarios.
• Gene sequencing should be considered for definitive diagnosis, especially in families with suspected complex SMN1 mutations.