X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases

Possible links between long-term geomagnetic variations and whole-mantle convection processes

The Earth's internal magnetic field varies on timescales of months to billions of years. The field is generated by convection in the liquid outer core, which in turn is influenced by the heat flowing from the core into the base of the overlying mantle. Much of the magnetic field's variation is thought to be stochastic, but over very long timescales, this variability may be related to changes in heat flow associated with mantle convection processes. Over the past 500 Myr, correlations between palaeomagnetic behaviour and surface processes were particularly striking during the middle to late Mesozoic era, beginning about 180 Myr ago. Simulations of the geodynamo suggest that transitions from periods of rapid polarity reversals to periods of prolonged stability — such as occurred between the Middle Jurassic and Middle Cretaceous periods — may have been triggered by a decrease in core–mantle boundary heat flow either globally or in equatorial regions. This decrease in heat flow could have been linked to reduced mantle-plume-head production at the core–mantle boundary, an episode of true polar wander, or a combination of the two