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. 2017 Sep 25;7(1):12288.
doi: 10.1038/s41598-017-11620-3.

The utility of Next Generation Sequencing for molecular diagnostics in Rett syndrome

Silvia Vidal  1 , Núria Brandi  2 , Paola Pacheco  1 , Edgar Gerotina  1 , Laura Blasco  1 , Jean-Rémi Trotta  3 , Sophia Derdak  3 , Maria Del Mar O'Callaghan  4   5   6 , Àngels Garcia-Cazorla  4   5   6 , Mercè Pineda  5 , Judith Armstrong  7   8   9 ; Rett Working Group
Collaborators, Affiliations

The utility of Next Generation Sequencing for molecular diagnostics in Rett syndrome

Silvia Vidal et al. Sci Rep. .

Erratum in

Abstract

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that almost exclusively affects girls and is totally disabling. Three genes have been identified that cause RTT: MECP2, CDKL5 and FOXG1. However, the etiology of some of RTT patients still remains unknown. Recently, next generation sequencing (NGS) has promoted genetic diagnoses because of the quickness and affordability of the method. To evaluate the usefulness of NGS in genetic diagnosis, we present the genetic study of RTT-like patients using different techniques based on this technology. We studied 1577 patients with RTT-like clinical diagnoses and reviewed patients who were previously studied and thought to have RTT genes by Sanger sequencing. Genetically, 477 of 1577 patients with a RTT-like suspicion have been diagnosed. Positive results were found in 30% by Sanger sequencing, 23% with a custom panel, 24% with a commercial panel and 32% with whole exome sequencing. A genetic study using NGS allows the study of a larger number of genes associated with RTT-like symptoms simultaneously, providing genetic study of a wider group of patients as well as significantly reducing the response time and cost of the study.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Comparison of main coverage metrics. Average of all samples analyzed for the four different approaches. (a) Bar plots with 95% confidence interval for the four approaches. Alignment metrics: passing filter (PF) reads; percentage of PF reads that aligned to the reference sequence; and percentage of PF reads that were aligned to the reference sequence with a mapping quality of Q20 or higher signifying. (b) Tukey boxplots: Mean read depth; percentage of bases covered at C1; and percentage of bases covered at C30.
Figure 2
Figure 2
Comparison of coverage in 17 RTT-like genes. Scatter plots of average of the coverage at C1 and C30 of all samples analyzed for the four different approaches.
Figure 3
Figure 3
Statistics results for genetic diagnosis. Each columns represents different detection methodology used (SS, HCP, TSO and WES) (a) Percentage and total of families characterized and unsolved by the four different approaches. (b) Percentage of patients with MECP2, CDKL5, FOXG1, other genes with pathogenic mutations and the unsolved cases for the Sanger Sequencing (SS) and the three NGS approaches. Total of mutations found are detailed in Table S2.
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