RNA sequencing resolves novel DYNC2H1 variants causing short-rib thoracic dysplasia type 3: Case report

Area of Science:

• Genetics
• Molecular Biology
• Medical Diagnostics

Background:

• Intronic variants outside canonical splice sites are difficult to interpret and may be an underreported cause of genetic disorders.
• Autosomal recessive DYNC2H1 variants cause short-rib thoracic dysplasia 3 (SRTD3), a heterogeneous condition with skeletal abnormalities.
• Interpreting variants of uncertain significance (VUS) is crucial for diagnosing rare genetic diseases.

Purpose of the Study:

• To investigate the diagnostic utility of RNA sequencing (RNA-Seq) in a case of SRTD3 with inconclusive genetic testing results.
• To identify the molecular mechanism underlying SRTD3 caused by compound heterozygous variants in DYNC2H1, including an intronic VUS.

Main Methods:

• Clinical genetic testing identified a frameshift variant and an intronic VUS in DYNC2H1.
• RNA sequencing (RNA-Seq) was performed on the patient and family.
• Analysis focused on identifying novel splice junctions and assessing gene expression levels.

Main Results:

• The proband presented with typical SRTD3 features, including polydactyly and thoracic anomalies.
• RNA-Seq revealed a novel splice junction caused by the intronic VUS in DYNC2H1.
• Significantly decreased DYNC2H1 gene expression was observed in the proband.

Conclusions:

• RNA sequencing is essential for interpreting complex intronic variants and diagnosing rare genetic disorders.
• This case underscores the diagnostic power of RNA-Seq in identifying the molecular basis of SRTD3.
• Utilizing RNA-Seq can lead to definitive diagnoses for patients with rare diseases after inconclusive clinical genetic testing.