Abstracts

Rationale: Classic Rett syndrome is a common cause of intellectual disability in females with onset of symptoms around 18 months of age. It is characterized by acquired microcephaly, developmental regression, seizures, ataxia, and stereotypic hand movements. Multiple forms of atypical (variant) Rett syndrome have been described in both females and males and can be challenging to differentiate from other neurodevelopmental disorders. However, it is critically important to molecularly diagnose MECP2 related-disorders as there can be implications for reproductive planning and long-term care.  Methods: We conducted a retrospective analysis of 70 patients with likely pathogenic or pathogenic variants (L/PVs) in the MECP2 gene identified by molecular diagnostic testing at our laboratory. Panel testing was completed for genes associated with either Rett syndrome (Rett-panel, 40%, 28/70 cases) or epilepsy-related disorders (Epi-panel, 60%, 42/70 cases). All panels included next-generation sequencing followed by Sanger sequencing confirmation of reportable variants and concurrent deletion/duplication testing using exon-level array CGH.  Clinical features, age of molecular diagnosis, and gender were analyzed for the 70 patients with L/PVs in MECP2. Results: Clinical information was received for 77% (54/70) of patients in this study. While the average age of diagnosis was 8 years, we observed that patients tested with an Epi-panel were diagnosed slightly younger (average of 7.3 years, CI at 95% is 5.1) compared to patients tested with the Rett-panel (average of 8.9 years, CI at 95% is 1.9). Patients tested with the Rett-panel were more likely to have classic features of Rett syndrome compared to patients tested with an Epi-panel:  Patients positive for MECP2 L/PVs were noted to be female (96% Rett-panel vs. 76% Epi-panel) and to have developmental delay (78% Rett-panel vs. 55% Epi-panel), regression (48% Rett-panel vs. 29% Epi-panel), microcephaly (26% Rett-panel vs. 13% Epi-panel), ataxia (26% Rett-panel vs. 3% Epi-panel), and atypical hand movements (22% Rett-panel vs. 6% Epi-panel). We observed that 16% (11/70) of the patients with MECP2 L/PVs were male and 90% (10/11) of these MECP2 positive males were tested using an Epi-panel. Overall, seizures (generalized, absence, and/or febrile) were noted in 63% (34/54) of MECP2 positive patients and were most common in patients tested with an Epi-panel (94%).  Additionally, focal seizures were only observed in patients tested by an Epi-panel (23%).  Conclusions: Our results support and highlight the importance of testing the MECP2 gene as part of epilepsy panels.  Broader testing of the MECP2 gene may aid in an earlier diagnoses of patients and identifying atypical Rett syndrome cases, particularly male patients presenting with epilepsy-related neurodevelopmental disorders. Funding: N/A