Journal Article

Unraveling MECP2 structural variants in previously elusive Rett syndrome cases through IGV interpretation

Safran, Amit, Hadar, Noam, Birk, Ohad S., Christodoulou, John, Agam, Nadav, Jean, Matan M., Heimer, Gali, Aminov, Ilana, Freund, Ofek, Kaur, Simran, Dolgin, Vadim, Ben-Zeev, Bruria, Poleg, Tomer

2025

Overview

Rett syndrome (RTT) is a severe neurodevelopmental disorder, with MECP2 mutations accounting for 90–95% of classic and 50–70% of atypical cases. However, many clinically diagnosed RTT patients remain without molecular diagnoses. While point mutations and large rearrangements in MECP2 are well studied, the role of small-intermediate structural variants (SVs) remains mostly elusive. Using standard short-read whole genome sequencing, we identified novel de novo SVs in three out of three previously unresolved RTT cases: a complex SV with two deletions ( ~ 5Kbp and ~60Kbp) and a ~105Kbp inversion; a ~200Kbp translocation; and a ~3Kbp deletion. These findings suggest that such elusive SVs might be a common cause for “ MECP2 -negative” RTT. Incorporating SV detection into routine genetic testing through bioinformatic analysis of short-read sequencing or manual review using IGV could improve diagnostic rates and expand our understanding of RTT and similar disorders.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 692/4017 / 692/699 / Age / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Child development / Cognition & reasoning / Constipation / Convulsions & seizures / Epigenetics / Epilepsy / Eye contact / Gene Function / Gene Therapy / Genes / Genetic analysis / Genetic engineering / Genetic testing / Genomes / Human Genetics / Hyperventilation / Internal Medicine / MeCP2 protein / Methyl-CpG binding protein / Mutation / Neurodevelopmental disorders / Point mutation / Rett syndrome / Sleep / Stereotypes / Whole genome sequencing