Even though comprehension of human physiology is crucial in the clinical setting, students frequently learn part of this subject using rote memory and then are unable to transfer knowledge to other contexts or to solve clinical problems. This study evaluated the impact of articulating the concept map strategy with the mediated learning experience on meaningful learning during the cardiovascular module of a medical physiology course at Universidad Autónoma de Bucaramanga. This research was based on the ideas of David Ausubel (meaningful learning), Joseph Novak (concept maps), and Reuven Feuerstein (mediated learning experience). Students were randomly allocated to either an intervention group (mediated learning experience articulated with concept mapping) or a control group (traditional methodology). The intervention group constructed concept maps related to cardiovascular physiology and used them to solve problems related to this subject. The control group attended traditional discussion sessions and problem-solving sessions. All students were evaluated with two types of exams: problem-solving and multiple-choice exams. The intervention group performed significantly better on the problem-solving exams, but the difference was not significant in the multiple-choice exam. It was concluded that intervention promoted meaningful learning that allowed the students to transfer this knowledge to solve problems. The implemented strategy had a greater impact on the students who came into the study with the lowest cognitive competence, possibly because they were empowered by the intervention.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

Coarctation of the aorta (CoA) and hypoplastic left heart syndrome (HLHS) have been reported in rare individuals with large terminal deletions of chromosome 15q26. However, no single gene important for left ventricular outflow tract (LVOT) development has been identified in this region. Using array-comparative genomic hybridization, we identified two half-siblings with CoA with a 2.2 Mb deletion on 15q26.2, inherited from their mother, who was mosaic for this deletion. This interval contains an evolutionary conserved, protein-coding gene, MCTP2 (multiple C2-domains with two transmembrane regions 2). Using gene-specific array screening in 146 individuals with non-syndromic LVOT obstructive defects, another individual with HLHS and CoA was found to have a de novo 41 kb intragenic duplication within MCTP2, predicted to result in premature truncation, p.F697X. Alteration of Mctp2 gene expression in Xenopus laevis embryos by morpholino knockdown and mRNA overexpression resulted in the failure of proper OT development, confirming the functional importance of this dosage-sensitive gene for cardiogenesis. Our results identify MCTP2 as a novel genetic cause of CoA and related cardiac malformations.

Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data was used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (> 1 MB) were observed in 33 probands (~3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically-relevant genomic disorder in a small but important proportion of these individuals.

Mucopolysaccharidosis type III, or Sanfilippo syndrome, is an autosomal recessive disorder characterized by impairment in the degradation of Heparan sulfate. Here the authors describe the natural history of 5 related individuals; all associated through a large pedigree which reports a total of 11 affected members, originally from the Boyacá region in Colombia, diagnosed with MPS IIIC who all harbor a novel mutation in HGSNAT. The authors report an unusually high incidence of the disease in this population. The clinical features are similar to previously described patients, although some differences in the degree of severity and end-stage of the disease are seen in this specific group. The authors consider that the high degree of endogamy in this specific population could underlie modifying factors for the severity of presentation in these patients. Future studies might provide more information on the functional effect of this novel mutation, which could define this group as a genetic isolate.