A novel AP1S2 variant causing leaky splicing in X-linked intellectual disability: Further delineation and intrafamilial variability
Issued Date
2024-01-01
Resource Type
ISSN
15524825
eISSN
15524833
Scopus ID
2-s2.0-85192048526
Pubmed ID
38682877
Journal Title
American Journal of Medical Genetics, Part A
Rights Holder(s)
SCOPUS
Bibliographic Citation
American Journal of Medical Genetics, Part A (2024)
Suggested Citation
Noojarern S., Tim-Aroon T., Anurat K., Phetthong T., Khongkraparn A., Wattanasirichaigoon D. A novel AP1S2 variant causing leaky splicing in X-linked intellectual disability: Further delineation and intrafamilial variability. American Journal of Medical Genetics, Part A (2024). doi:10.1002/ajmg.a.63639 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/98321
Title
A novel AP1S2 variant causing leaky splicing in X-linked intellectual disability: Further delineation and intrafamilial variability
Corresponding Author(s)
Other Contributor(s)
Abstract
Pettigrew syndrome (PGS), an X-linked intellectual disability (XLID), is caused by mutations in the AP1S2 gene. Herein, we described a Thai family with six patients who had severe-to-profound intellectual impairment, limited verbal communication, and varying degrees of limb spasticity. One patient had a unilateral cataract. We demonstrated facial evolution over time, namely coarse facies, long faces, and thick lip vermilions. We identified a novel AP1S2 variant, c.1-2A>G. The mRNA analysis revealed that the variant resulted in splicing defects with leaky splicing, yielding two distinct aberrant transcripts, one of which likely resulting in the mutant protein lacking the first 44 amino acids whereas the other possibly leading to no production of the protein. By performing a literature review, we found 51 patients and 11 AP1S2 pathogenic alleles described and that all the variants were loss-of-function alleles. The severity of ID in Pettigrew syndrome is mostly severe-to-profound (54.8%), followed by moderate (26.2%) and mild. Progressive spasticity was noted in multiple patients. In summary, leaky splicing found in the present family was likely related to the intrafamilial clinical variability. Our data also support the previous notion of variable expression and neuroprogressive nature of the disorder.