Massive parallel sequencing identifies RAPSN and PDHA1 mutations causing fetal akinesia deformation sequence
Lore Winters1, Evelien Van Hoof2, Luc De Catte3
1Department of Pediatrics, University Hospitals Leuven, Catholic University Leuven, Leuven, Belgium.
Summary
Next-generation sequencing identified genetic causes for fetal akinesia deformation sequence (FADS) and arthrogryposis multiplex congenita (AMC). This diagnostic approach identified novel mutations in RAPSN and PDHA1 genes, improving genetic counseling for affected families.
Area of Science:
- Genetics
- Molecular Biology
- Medical Diagnostics
Background:
- Fetal akinesia deformation sequence (FADS) and arthrogryposis multiplex congenita (AMC) present diagnostic challenges due to clinical and genetic heterogeneity.
- Traditional sequencing methods are often insufficient for identifying the genetic causes of FADS/AMC.
Observation:
- Next-generation sequencing (NGS) using a custom gene panel was applied to two fetuses with FADS.
- The study employed a tiered approach, analyzing a broad disease-associated gene panel followed by a specific arthrogryposis/fetal akinesia subpanel if necessary.
Findings:
- A homozygous RAPSN mutation (c.484G>A) was identified as the cause of FADS in the first family.
- A de novo hemizygous PDHA1 splice-site mutation (c.498C>T) was found in a sporadic patient with FADS and brain anomalies.
- This study reports the first association of the specific RAPSN mutation with FADS and the first case of AMC linked to a PDHA1 mutation.
Implications:
- NGS-based gene panels are effective for diagnosing genetically heterogeneous conditions like AMC/FADS.
- The findings expand the known genetic spectrum for FADS, including a novel RAPSN mutation and implicating PDHA1 mutations.
- Early and accurate genetic diagnosis facilitates improved genetic counseling and management for families affected by FADS/AMC.
