The utility of exome sequencing in diagnosing pediatric neurodevelopmental disorders in a highly consanguineous population.

Exome sequencing (ES) has been utilized in diagnosing children with neurodevelopmental manifestations, this study aimed to investigate the utility of ES in children within a highly consanguineous population that presented with neurodevelopmental complaints. A retrospective chart review was performed for 405 children with neurodevelopmental complaints who have had ES and were evaluated in multiple centers in the United Arab Emirates over a four-year period. Within the cohort of 405 children, consanguinity was reported in 35% (144/405). The primary clinical presentations were developmental delay/cognitive impairment, distinctive facial features, hypotonia, seizures, and weakness. The diagnostic yield was 57% (231/405). Novel variants were identified in 54% (125/231) of positive cases. Within the positive cases, specific treatment was available in 6% (13/231) and copy number variants (CNV) were reported in 3% (8/231) of cases. In eight children, variants in genes that have not yet been linked to human disease that could potentially be the cause of the observed phenotype "candidate genes" were identified. ES was utilized effectively within this cohort with a high diagnostic yield and through the identification of novel gene variants, CNVs, candidate genes and secondary findings as well as the alteration of the treatment plan in cases where treatment was available.

Disorders of histone methylation: Molecular basis and clinical syndromes.

Epigenetic modifications of DNA and histone tails are essential for gene expression regulation. They play an essential role in neurodevelopment as nervous system development is a complex process requiring a dynamic pattern of gene expression. Histone methylation is one of the vital epigenetic regulators and mostly occurs on lysine residues of histones H3 and H4. Histone methylation is catalyzed by two sets of enzymes: histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). KMT2 enzymes form a distinct multi-subunit complex known as COMPASS to enhance their catalytic activity and diversify their biologic functions. Several neurodevelopmental syndromes result from defects in histone methylation which can be caused by deficiencies in histone methyltransferases and demethylases, loss of the histone methyltransferase activator TASP1, or derangements in COMPASS formation. In this review article, the molecular mechanism of histone methylation is discussed followed by summarizing clinical syndromes caused by monogenic defects in histone methylation.

A homozygous frame-shift variant in PROSER1 is associated with developmental delay, hypotonia, genitourinary malformations, and distinctive facial features.

We report four children from three related families who presented with a similar phenotype characterized by developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, and genitourinary malformations. They also shared common facial features including arched eyebrows, prominent eyes, broad nasal bridge, low-hanging columella, open mouth, thick lower lip, protruding tongue, large low-set ears, and parietal bossing. Exome sequencing for affected individuals revealed a homozygous frame-shift variant, c.1833del; p.(Thr612Glnfs*22), in PROSER1 which encodes the proline and serine rich protein 1 (PROSER1). PROSER1 has recently been found to be part of the histone methyltransferases KMT2C/KMT2D complexes. PROSER1 stabilizes TET2, a member of the TET family of DNA demethylases which is involved in recruiting the enhancer-associated KMT2C/KMT2D complexes and mediating DNA demethylation, activating gene expression. Therefore, PROSER1 may play vital and potentially general roles in gene regulation, consistent with the wide phenotypic spectrum observed in the individuals presented here. The consistent phenotype, the loss-of-function predicted from the frame-shift, the co-segregation of the phenotype in our large pedigree, the vital role of PROSER1 in gene regulation, and the association of related genes with neurodevelopmental disorders argue for the loss of PROSER1 to be the cause for a novel recognizable syndrome.

Effect of Sleeping Disorders on the Growth Parameters of Lebanese Children.

Background: Sleep is a vital physiological function for the maintenance of health and quality of life by ensuring body rest and restoring its energy levels. Remarkably, some children have sleep disordered breathing (SDB) that can disturb their normal sleep and affect the quality of their lives. Objective: The aim of this study was to assess the correlation between SDB and growth impairments and wether the growth parameters vary among genders. Methods: This study was conducted in two steps: 1500 questionnaires were distributed to children aged 3 to 12 years. The questionnaire covered personal information, medical history, and the Pediatric Sleep Questionnaire. The latter was used to evaluate the incidence of sleep-disordered breathing and was completed by parents of the involved children. Growth assessment was then determined for the population to find the correlation between sleep disorders and growth impairments. Results: A total of 931 completed questionnaires were returned (70.7% response rate). Among the respondents, 56.3% were females whereas 43.3% were males. The mean age was 8 years. The result showed that 16.11% of children were at high risk of sleep-disordered breathing. A significant effect of SDB syndrome on growth parameters (weight-for-age parameter z-score and BMI for age z-score) was observed among males. Concerning the weight for age z-score, a significant difference was found between the means of control and SDB individuals (P = 0.0302). In male groups, the difference was significant (P=0.043), while non-significant difference was found in female groups (P = 0.69). Conclusion: This study highlights a significant effect of SDB on growth parameters among males aged between 3 and 12 years.

Mitochondrial Fission and Fusion: Molecular Mechanisms, Biological Functions, and Related Disorders.

Mitochondria are dynamic organelles that undergo fusion and fission. These active processes occur continuously and simultaneously and are mediated by nuclear-DNA-encoded proteins that act on mitochondrial membranes. The balance between fusion and fission determines the mitochondrial morphology and adapts it to the metabolic needs of the cells. Therefore, these two processes are crucial to optimize mitochondrial function and its bioenergetics abilities. Defects in mitochondrial proteins involved in fission and fusion due to pathogenic variants in the genes encoding them result in disruption of the equilibrium between fission and fusion, leading to a group of mitochondrial diseases termed disorders of mitochondrial dynamics. In this review, the molecular mechanisms and biological functions of mitochondrial fusion and fission are first discussed. Then, mitochondrial disorders caused by defects in fission and fusion are summarized, including disorders related to MFN2, MSTO1, OPA1, YME1L1, FBXL4, DNM1L, and MFF genes.

National Board of Medical Examiners and Curriculum Change: What Do Scores Tell Us? A Case Study at the University of Balamand Medical School.

OBJECTIVES: This study describes the results of NBME (National Board of Medical Examiners) implementation in Balamand Medical School (BMS) from 2015 to 2019, after major curricular changes were introduced as of 2012. BMS students' performance was compared with the international USMLE step 1 (United States Medical Licensing Examination, herein referred to as step 1) cohorts' performances. The BMS students' NBME results were analyzed over the successive academic years to assess the impact of the serial curricular changes that were implemented. METHODS: This longitudinal study describes the performance of BMS preclinical second year medicine (Med II) students on all their NBME exams over 4 academic years starting 2015-2016 to 2018-2019. These scores were compared with the step 1 comparison group scores using item difficulty. The t test was computed for each of the NBME exams to check whether the scores' differences were significant. RESULTS: Results revealed that all BMS cohorts scored lower than the international USMLE step 1 comparison cohorts in all disciplines across the 4 academic years except Psychiatry. However, the results were progressively approaching step 1 results, and the difference between step 1 scores and BMS students' NBME scores became closer and not significant as of year 4. CONCLUSIONS: The results of the study are promising. They show that the serial curricular changes enabled BMS Med II students' scores to reach the international cohorts' scores after 4 academic years. Moreover, the absence of statistical difference between cohort 4 scores and step 1 cohorts is not module dependent and applies to all clinical modules. Further studies should be conducted to assess whether the results obtained for cohort 4 can be maintained.