Splicing Alterations Associated with Multiple Homozygous TNXB Variants in a Patient with Suspected Classical-Like Ehlers-Danlos Syndrome.
Bunta Imanaka, Yuiko Hasegawa, Kazumi Kawato et al.
✦ AI-curated · Sources linked
Case in brief
A patient with generalized joint hypermobility, soft, pliable skin, recurrent elbow dislocations, orthostatic dizziness, chronic constipation, and mild mitral valve regurgitation was evaluated for suspected Ehlers-Danlos syndrome. Testing identified multiple homozygous TNXB variants and a mosaic variant. Patient-derived RNA and mutant minigene assays showed alternative splicing with intron 40 retention alongside the normal transcript. Retention was more pronounced with multiple variants and was most prominent with c.12,210 + 5G > A. The resulting in-frame transcripts are predicted to affect the fibrinogen C-terminal domain, but the clinical significance of the variants remains uncertain.
What made this case unusual
Functional assays linked multiple TNXB variants to intron 40 retention, with c.12,210 + 5G > A most prominently associated with the effect in minigene assays; the aberrant transcripts were in-frame.
Diagnostic / clinical pearl
For suspected clEDS with uncertain TNXB variants, interpret genetic findings alongside the clinical assessment and population frequency data; RNA and minigene analyses can help assess potential splicing effects.