Intragenic inversions in NF1 gene as pathogenic mechanism in neurofibromatosis type 1.
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:
11 2022
11 2022
Historique:
received:
24
09
2021
accepted:
05
07
2022
revised:
28
06
2022
pubmed:
26
7
2022
medline:
4
11
2022
entrez:
25
7
2022
Statut:
ppublish
Résumé
Neurofibromatosis type 1 (NF1), an autosomal dominant disorder characterized by skin pigmentary lesions and multiple cutaneous neurofibromas, is caused by neurofibromin 1 (NF1) loss of function variants. Currently, a molecular diagnosis is frequently established using a multistep protocol based on cDNA and gDNA sequence analysis and/or Multiplex Ligation-dependent Probe Amplification (MLPA) assay on genomic DNA, providing an overall detection rate of about 95-97%. The small proportion of clinically diagnosed patients, which at present do not obtain a molecular confirmation likely are mosaic, as their pathogenic variant may remain undetected due to low sensitivity of low coverage NGS approaches, or they may carry a type of pathogenic variant refractory to currently used technologies. Here, we report two unrelated patients presenting with two different inversions that disrupt the NF1 coding sequence, resulting in an NF1 phenotype. In one subject, the inversion was associated with microdeletions spanning a few NF1 exons at both breakpoints, while in the other the rearrangement did not cause exon loss, thus testing negative by MLPA assay. Considering the high proportion of repeated regions within the NF1 sequence, we propose that intragenic structural rearrangements should be considered as possible pathogenic mechanisms in patients fulfilling the NIH diagnostic criteria of NF1 but lacking of molecular confirmation and in patients with NF1 intragenic microdeletions.
Identifiants
pubmed: 35879407
doi: 10.1038/s41431-022-01153-3
pii: 10.1038/s41431-022-01153-3
pmc: PMC9626576
doi:
Substances chimiques
Neurofibromin 1
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1239-1243Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.
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