De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females.

PURPOSE: MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes. METHODS: By international matchmaking we assembled variant and clinical data on 18 females presenting with variable neurodevelopmental disorders (NDDs) and harboring de novo variants in MED12. RESULTS: Five nonsense variants clustered in the C-terminal region, two splice variants were found in the same exon 8 splice acceptor site, and 11 missense variants were distributed over the gene/protein. Protein truncating variants were associated with a severe, syndromic phenotype consisting of intellectual disability (ID), facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. De novo missense variants were associated with a less specific, but homogeneous phenotype including severe ID, autistic features, limited speech and variable other anomalies, overlapping both with females with truncating variants as well as males with missense variants. CONCLUSION: We establish de novo truncating variants in MED12 as causative for a distinct NDD and de novo missense variants as causative for a severe, less specific NDD in females.

Correction: Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability.

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Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability.

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.

High-displacement piezoelectric actuator utilizing a meander-line geometry I. Experimental characterization.

The compact linear-motion piezoelectric actuator developed has relatively large displacement capabilities. It is composed of a number of parallel bars of lead zirconium titanate (PZT) connected together in a meander-line configuration so that they are mechanically in series and electrically in parallel. The polarity of the adjacent bars is arranged so that if a given bar expands under the applied voltage, the adjacent bars contract. An electromechanical model of the actuator predicted and measurements verified that stiffeners added to the basic meander line geometry significantly increased the force output without affecting the displacement versus applied voltage relationship.

A linear piezoelectric stepper motor with submicrometer step size and centimeter travel range.

A linear stepper motor capable of submicrometer controlled movement has been constructed using the piezoelectric material lead zirconate titanate (PZT). This motor consists of a 25.4-mmx12.7-mmx1.6-mm piezoelectric driving element connected between a glider base and an attached load. The device is inset in a trench to constrain motion to one dimension. An electrode on the bottom of the glider is used with an electrode on the top of the trench to implement an electrostatic clamp. This clamp enables the stepper motor to climb slopes of up to 12 degrees , whereas without the clamp only slopes of 6 degrees or less are tolerated. A linear inertial sliding motion can be achieved by expanding and contracting the piezoelectric bar, but the addition of the electrostatic clamp enhances the movement capabilities of the glider by the periodic clamping and unclamping of the glider. Glider velocities of 5.7-476 mum/s are measured by timing the movement of the glider over a 1.0-mm portion of the track through an optical microscope. Displacement steps of 0.07-1.1 mum are calculated by dividing the measured glider velocity by the frequency of the applied voltage pulses. Displacement step size and glider velocity are controlled by the application of PZT extension voltages ranging from +/-(60-340) V.

Microdevices in medicine.

The application of microelectromechanical systems (MEMS) to medicine is described. Three types of biomedical devices are considered, including diagnostic microsystems, surgical microsystems, and therapeutic microsystems. The opportunities of MEMS miniaturization in these emerging disciplines are considered, with emphasis placed on the importance of the technology in providing a better outcome for the patient and a lower overall health care cost. Several case examples in each of these areas are described. Key aspects of MEMS technology as it is applied to these three areas are described, along with some of the fabrication challenges.