Mosaicism of common pathogenic MECP2 variants identified in two males with a clinical diagnosis of Rett syndrome.
MECP2
NGS
Rett syndrome
digital PCR
male
mosaicism
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
revised:
31
05
2022
received:
22
03
2022
accepted:
07
07
2022
pubmed:
5
8
2022
medline:
15
9
2022
entrez:
4
8
2022
Statut:
ppublish
Résumé
Rett (RTT) syndrome, a neurodevelopmental disorder caused by pathogenic variation in the MECP2 gene, is characterized by developmental regression, loss of purposeful hand movements, stereotypic hand movements, abnormal gait, and loss of spoken language. Due to the X-linked inheritance pattern, RTT is typically limited to females. Recent studies revealed somatic mosaicism in MECP2 in male patients with RTT-like phenotypes. While detecting mosaic variation using Sanger sequencing is theoretically possible for mosaicism over ~15%-20%, several variables, including efficiency of PCR, background noise, and/or human error, contribute to a low detection rate using this technology. Mosaic variants in two males were detected by next generation sequencing (NGS; Case 1) and by Sanger re-sequencing (Case 2). Both had targeted digital PCR (dPCR) to confirm the variants. In this report, we present two males with classic RTT syndrome in whom we identified pathogenic variation in the MECP2 gene in the mosaic state (c.730C > T (p.Gln244*) in Patient 1 and c.397C > T (p.Arg133Cys) in Patient 2). In addition, estimates and measures of mosaic variant fraction were surprisingly similar between Sanger sequencing, NGS, and dPCR. The mosaic state of these variants contributed to a lengthy diagnostic odyssey for these patients. While NGS and even Sanger sequencing may be viable methods of detecting mosaic variation in DNA or RNA samples, applying targeted dPCR to supplement these sequencing technologies would provide confirmation of somatic mosaicism and mosaic fraction.
Identifiants
pubmed: 35924478
doi: 10.1002/ajmg.a.62913
doi:
Substances chimiques
MECP2 protein, human
0
Methyl-CpG-Binding Protein 2
0
DNA
9007-49-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2988-2998Informations de copyright
© 2022 Wiley Periodicals LLC.
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