Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth
Sofia Frisk1,2, Fulya Taylan1, Izabela Blaszczyk3
1Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Clinical Genetics
|March 29, 2019
Summary
PIK3CA-related overgrowth spectrum involves rare genetic disorders causing asymmetric overgrowth. This study identifies somatic PIK3CA mutations in ectopic muscles, linking mutation timing to disease phenotype.
Area of Science:
- Genetics
- Developmental Biology
- Pathology
Background:
- PIK3CA-related overgrowth spectrum (PROS) comprises rare genetic disorders characterized by asymmetric overgrowth due to somatic mosaic PIK3CA mutations.
- Congenital muscular upper limb overgrowth with aberrant anatomy presents a diagnostic challenge.
Purpose of the Study:
- To report clinical and molecular findings in two patients with PROS manifesting as congenital muscular upper limb overgrowth.
- To investigate the role of PIK3CA mutations in ectopic muscle development and their correlation with disease phenotype.
Main Methods:
- Clinical data collection from two patients with muscular upper limb overgrowth.
- Surgical biopsy of hypertrophic ectopic muscles.
- DNA sequencing and digital polymerase chain reaction (dPCR) for PIK3CA mutation identification.
Main Results:
- Two patients diagnosed with PROS presented with congenital muscular upper limb overgrowth and numerous ectopic muscles.
- Somatic mosaic PIK3CA hotspot mutations (c.3140A>G, p.(His1047Arg) and c.1624G>A, p.(Glu542Lys)) were identified in ectopic muscle biopsies.
- Patient 2, with bilateral overgrowth and 13 ectopic muscles, suggests an earlier mutation occurrence in the pre-somitic mesoderm.
Conclusions:
- PIK3CA mutations are present in ectopic muscles, underscoring PIK3CA's role in early human embryonic cell fate.
- The timing of PIK3CA mutagenesis during embryogenesis significantly influences the resulting disease phenotype.
- Confirms PIK3CA-related muscular overgrowth with ectopic accessory muscles as a distinct diagnostic entity.
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