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A novel variant in AFF3 underlying isolated syndactyly
Hammal Khan1, Glenn Koh2, Angie En Qi Chong2
1Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan.
Clinical Genetics
|October 23, 2022
Summary
A new genetic variant in the AFF3 gene was identified in a family with syndactyly, a common limb malformation. This discovery suggests a potential loss-of-function mechanism for this novel variant in limb development.
Area of Science:
- Genetics
- Developmental Biology
- Molecular Biology
Background:
- Syndactyly is a prevalent limb malformation with an incompletely understood genetic basis.
- The AFF3 gene, encoding a nuclear transcription factor, plays a role in limb development.
Purpose of the Study:
- To identify the genetic cause of isolated syndactyly in a multiplex family.
- To investigate the functional impact of a novel AFF3 variant.
Main Methods:
- Whole exome sequencing was employed to identify genetic variants.
- Functional studies, including protein stability, subcellular localization assays, and zebrafish overexpression models, were performed.
Main Results:
- A novel heterozygous missense variant (c.2915G>C: p.Arg972Pro) in AFF3 was identified in affected family members.
- Functional studies indicated that the Arg972Pro variant acts as a loss-of-function allele.
- The variant is located in the C-terminal region of AFF3, previously unlinked to human disorders.
Conclusions:
- The identified AFF3 variant is associated with isolated syndactyly.
- Loss-of-function variants in the AFF3 C-terminus may lead to a distinct phenotype compared to previously described AFF3 mutations.
- This finding expands the known genetic etiology of syndactyly.
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