Loss of function of ADNP by an intragenic inversion.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
14
11
2022
accepted:
15
02
2023
revised:
06
02
2023
pmc-release:
01
08
2024
medline:
7
8
2023
pubmed:
25
2
2023
entrez:
24
2
2023
Statut:
ppublish
Résumé
ADNP is a well-known gene implicated in intellectual disability and its molecular spectrum consists mainly in loss of function variant in the ADNP last and largest exon. Here, we report the first description of a patient with intellectual disability identified with an intragenic inversion in ADNP. RNAseq experiment showed a splice skipping of the inversed exons. Moreover, in-silico analysis of initiating ATGs in the mutated transcript using contextual Kozak score suggested that several initiating ATGs were likely used to translate poisonous out-of-frame ORFs and would lead to the suppression of any in-frame rescuing translation, thereby causing haploinsufficiency. As constitutive Alu sequences with high homology were identified at both breakpoints in reversed orientation in the reference genome, we hypothesized that Alu-mediated non-allelic-homologous recombination was responsible for this rearrangement. Therefore, as this inversion is not detectable by exome sequencing, this mechanism could be a potential underdiagnosed recurrent mutation in ADNP-related disorders.
Identifiants
pubmed: 36828924
doi: 10.1038/s41431-023-01323-x
pii: 10.1038/s41431-023-01323-x
pmc: PMC10400548
doi:
Substances chimiques
ADNP protein, human
0
Homeodomain Proteins
0
Nerve Tissue Proteins
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
967-970Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.
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