Bi-allelic truncating mutations in VWA1 cause neuromyopathy.

The von Willebrand Factor A domain containing 1 protein, encoded by VWA1, is an extracellular matrix protein expressed in muscle and peripheral nerve. It interacts with collagen VI and perlecan, two proteins that are affected in hereditary neuromuscular disorders. Lack of VWA1 is known to compromise peripheral nerves in a Vwa1 knock-out mouse model. Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder. We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent. Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature.

New euchromatic variant dup(11)(p15.3p15.1) transmitted through two generations defined by low coverage whole genome sequencing.

We report on a 14-year old boy, his father, and his paternal uncle, all three carriers of a duplication of chromosomal region 11p15.3-p15.1. The aberration was transmitted by the grandmother, who is carrier of a balanced insertion 46,XX,ins(14;11)(q32.1;p15.3p15.1). In order to determine the precise molecular basis of this structural variant, we performed low-coverage whole genome sequencing on the boy's father. This approach allowed precise determination of the genomic breakpoints and revealed a duplication of 6.9 Mb, centromeric to the Beckwith-Wiedemann/Silver-Russell syndrome critical region in 11p15.5, that inserted in inverse orientation into 14q32.12 (according to HGVS nomenclature: NC_000014.8:g.92871000_92871001ins[NC_000011.9:g.12250642_19165928inv;T]). To our knowledge, this is the first report of a duplication of 11p15.3-p15.1 involving more than 40 genes and transmitted through two generations without apparent clinical effects.

The impact of an audience response system on a summative assessment, a controlled field study.

BACKGROUND: Audience response systems allow to activate the audience and to receive a direct feedback of participants during lectures. Modern systems do not require any proprietary hardware anymore. Students can directly respond on their smartphone. Several studies reported about a high level of satisfaction of students when audience response systems are used, however their impact on learning success is still unclear. METHODS: In order to evaluate the impact of an audience response system on the learning success we implemented the audience response system eduVote into a seminar series and performed a controlled crossover study on its impact on assessments. One hundred fifty-four students in nine groups were taught the same content. In four groups, eduVote was integrated for the first topic while five groups were taught this topic without the audience response systems. For a second topic, the groups were switched: Those groups who were taught before using eduVote were now taught without the audience response system and vice versa. We then analysed the impact of the audience response system on the students' performance in a summative assessment and specifically focused on questions dealing with the topic, for which the audience response system was used during teaching. We further assessed the students' perception on the use of eduVote using questionnaires. RESULTS: In our controlled crossover study we could not confirm an impact of the audience response system eduVote on long-term persistence i.e. the students' performance in the summative assessment. Our evaluation revealed that students assessed the use of eduVote very positively, felt stronger engaged and better motivated to deal with the respective topics and would prefer their integration into additional courses as well. In particular we identified that students who feel uncomfortable with answering questions in front of others profit from the use of an audience response system during teaching. CONCLUSIONS: Audience response systems motivate and activate students and increase their engagement during classes. However, their impact on long-term persistence and summative assessments may be limited. Audience response systems, however, specifically allow activating students which cannot be reached by the traditional way of asking questions without such an anonymous tool.

Xq22.3-q23 deletion including ACSL4 in a patient with intellectual disability.

Mutations or deletions of ACSL4 (FACL4, OMIM 300157) are a rare cause of non-syndromic X-linked intellectual disability. We report on a 10-year-old male patient with moderate intellectual disability, sensorineural hearing loss, facial dysmorphism, pyloric stenosis, and intestinal obstruction in whom a de novo Xq22.3-q23 deletion was detected by SNP array analysis. The deleted 1.56 Mb interval harbored ACSL4 and eight neighboring genes (GUCY2F, NXT2, KCNE1L, TMEM164, MIR3978, AMMECR1, SNORD96B, and RGAG1). In contrast to previously reported patients with chromosome aberrations in the region of the AMME complex (Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis, OMIM 300194), this deletion did not contain the Alport syndrome gene COL4A5, suggesting that loss of one or several of the other genes in this interval is responsible for the clinical problems. In summary, the patient reported here broadens our knowledge of the phenotypic consequences of deletions of chromosome region Xq22.3-q23 and provides further proof for ACSL4 as an X-linked intellectual disability gene.