Rett Syndrome, a Neurodevelopmental Disorder, Whole-Transcriptome, and Mitochondrial Genome Multiomics Analyses Identify Novel Variations and Disease Pathways.

Rett syndrome (RTT) is a severe neurodevelopmental disorder reported worldwide in diverse populations. RTT is diagnosed primarily in females, with clinical findings manifesting early in life. Despite the variable rates across populations, RTT has an estimated prevalence of ∼1 in 10,000 live female births. Among 215 Saudi Arabian patients with neurodevelopmental and autism spectrum disorders, we identified 33 patients with RTT who were subsequently examined by genome-wide transcriptome and mitochondrial genome variations. To the best of our knowledge, this is the first in-depth molecular and multiomics analyses of a large cohort of Saudi RTT cases with a view to informing the underlying mechanisms of this disease that impact many patients and families worldwide. The patients were unrelated, except for 2 affected sisters, and comprised of 25 classic and eight atypical RTT cases. The cases were screened for methyl-CpG binding protein 2 (MECP2), CDKL5, FOXG1, NTNG1, and mitochondrial DNA (mtDNA) variants, as well as copy number variations (CNVs) using a genome-wide experimental strategy. We found that 15 patients (13 classic and two atypical RTT) have MECP2 mutations, 2 of which were novel variants. Two patients had novel FOXG1 and CDKL5 variants (both atypical RTT). Whole mtDNA sequencing of the patients who were MECP2 negative revealed two novel mtDNA variants in two classic RTT patients. Importantly, the whole-transcriptome analysis of our RTT patients' blood and further comparison with previous expression profiling of brain tissue from patients with RTT revealed 77 significantly dysregulated genes. The gene ontology and interaction network analysis indicated potentially critical roles of MAPK9, NDUFA5, ATR, SMARCA5, RPL23, SRSF3, and mitochondrial dysfunction, oxidative stress response and MAPK signaling pathways in the pathogenesis of RTT genes. This study expands our knowledge on RTT disease networks and pathways as well as presents novel mutations and mtDNA alterations in RTT in a population sample that was not previously studied.

Interest and perceived barriers toward careers in academic medicine among medical students at Alfaisal University - College of Medicine: A Saudi Arabian perspective.

AIMS: [1] Identify the percentage of undergraduate students who are interested in academic medicine (AM) careers, [2] Explore the relationship between students' characteristics, previous experiences and interest in AM careers and [3] Determine students' perceived barriers toward AM careers at Alfaisal University - College of Medicine. METHODS: An online, anonymous, random, self-rating survey was administered during spring 2013-2014 to second-year and third-year students (n = 302). Chi-square test was used to correlate between interest in AM careers and students' characteristics. Mann-Whitney U-test was used to compare the mean 5-point Likert scale responses between male and female students. RESULTS: A total of 231 students participated in the survey (response rate: 76.5%). A total of 32 students (13.9%) expressed interest in AM careers, and this percentage significantly differed by gender, academic year, interest in teaching and research and previous research experiences (p < 0.05). The top three barriers were "lower income" (77.5%), "competing pressures to fulfill clinical-teaching-research duties" (73.6%) and "lack of career advising" (69.7%). As opposed to males, females achieved higher statistically significant differences of means regarding: "competing pressures to fulfill clinical-teaching-research duties" (p < 0.001) and "lack of same-gender role models in AM careers" (p < 0.000). CONCLUSIONS: AM careers were unpopular by students. Curricular, extracurricular and institutional measures should be implemented to rectify this dilemma.