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.

Effects of position on respiratory muscle function during CO2 rebreathing.

The effects of changing from the sitting to supine position on respiratory muscle function was assessed during CO2 rebreathing. Gastric (Pg), pleural (Ppl) and transdiaphragmatic (Pdi) pressures and thoracoabdominal motion were monitored. Diaphragmatic EMG was measured by a bipolar esophageal electrode and quantitated as a moving time average (EMGdi). From sitting to supine, in only 2 of 7 subjects (group A) the diaphragm gained a mechanical advantage as evident by an increased slope of the Pdi versus EMGdi relationship not present in the other 5 subjects (group B). At high levels of ventilation while sitting, only group B increased expiratory abdominal muscle activity leading to a more favorable diaphragm length and a passive descent of the abdomen-diaphragm on inspiration. In the supine position functional residual capacity progressively increased in all subjects and the above abdominal pattern was not seen. We conclude that during upright CO2 rebreathing the recruitment of the expiratory abdominal muscles assists diaphragmatic function by placing the diaphragm in an advantageous pressure generating configuration.

Diaphragmatic EMG and transdiaphragmatic pressure measurements with a single catheter.

A single gastroesophageal catheter was used for simultaneous measurements of diaphragmatic electromyogram (EMGdi), esophageal, and gastric pressures in 10 normal volunteers. The catheter consisted of 2 polyethylene tubes, each with an outer diameter of 1.70 mm and an inner diameter of 1.19 mm, 2 platinum wire coils, and esophageal and gastric latex balloons. In all subjects studied, the increase in EMGdi, quantified as the average rate of rise of inspiratory moving average activity, and transdiaphragmatic pressure (Pdi) were linearly related to the increase in end-tidal PCO2 during CO2 rebreathing (range of r, 0.88 to 0.99 and 0.85 to 0.99, respectively). The relation between changes in EMGdi and that of Pdi, mean inspiratory flow, and occlusion pressure were also linear (range of r, 0.83-0.99, 0.73-0.99, and 0.84-0.99, respectively), indicating reliable recordings of EMGdi and Pdi during CO2 rebreathing in upright normal humans.

Diaphragmatic and genioglossal electromyogram responses to isocapnic hypoxia in humans.

In order to define the relationship between central control of upper airway and respiratory muscle function, diaphragmatic electromyogram (EMGdi) and genioglossal EMG (EMGge) responses to isocapnic hypoxia were studied in 6 awake supine volunteers. Both EMGs were processed and quantitated as moving time average activity. In all subjects, EMGge showed phasic inspiratory activity synchronous with EMGdi. Increases seen in EMGdi and EMGge were linearly related to the decrease in oxygen saturation (r = 0.89 +/- 0.08 and 0.89 +/- 0.08, respectively). There was also a linear relationship between the relative responses of both EMGs to hypoxia such that a low EMGdi response was associated with a low EMGge response and vice versa (r = 0.92, p less than 0.001). These results indicated that the genioglossus muscle behaves like a respiratory muscle and suggested that central control of upper airway and respiratory muscles in humans are intimately related.

Diaphragmatic and genioglossal electromyogram responses to CO2 rebreathing in humans.

To assess the relationship between central control of upper airway and respiratory muscle, simultaneously recorded diaphragmatic electromyogram (EMGdi) and genioglossal EMG (EMG ge) responses to CO2 rebreathing were compared in five supine volunteers. Both EMGs were quantitated in terms of inspiratory peak moving time-average activity. In all subjects both EMGdi and EMGge increased linearly with increasing alveolar CO2 pressure (r = 0.93 +/- 0.04 and 0.87 +/- 0.07, respectively), resulting in a significantly linear EMGge vs. EMGdi relationship (r = 0.91 +/- 0.04). CO2 response slopes of both EMGs were similar and linearly related (r = 0.96, P less than 0.001) such that subjects with low EMGdi response also had a low EMGge response and vice versa. Although the onset of EMGge activity preceded that of EMGdi, and the pattern of both EMGs were different, inspiration duration of both EMGs were similar. These data indicate that in humans both diaphragm and genioglossus muscle share similar control mechanisms and suggest that upper airway function is intimately related to the regulation of breathing.