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

Turing Machines for dummies: why representations do matter

Various methods exists in the litearture for denoting the configuration of a Turing Machine. A key difference is whether the head position is indicated by some integer (mathematical representation) or is specified by writing the machine state next to the scanned tape symbol (intrinsic representation). From a mathematical perspective this will make no difference. However, since Turing Machines are primarily used for proving undecidability and/or hardness results these representations do matter. Based on a number of applications we show that the intrinsic representation should be preferred

Data from: On the occurrence of three non-native cichlid species including the first record of a feral population of Pelmatolapia (Tilapia) mariae (Boulenger, 1899) in Europe

Thermally influenced freshwater systems provide suitable conditions for non-native species of tropical and subtropical origin to survive and form proliferating populations beyond their native ranges. In Germany, non-native convict cichlids (Amatitlania nigrofasciata) and tilapia (Oreochromis sp.) have established populations in the Gillbach, a small stream that receives warm water discharge from a local power plant. Here, we report on the discovery of spotted tilapia (Pelmatolapia mariae) in the Gillbach, the first record of a reproducing population of this species in Europe. It has been hypothesized that Oreochromis sp. in the Gillbach are descendants of aquaculture escapees and our mtDNA analysis found both O. mossambicus and O. niloticus maternal lineages, which are commonly used for hybrids in aquaculture. Convict cichlids and spotted tilapia were most probably introduced into the Gillbach by aquarium hobbyists. Despite their high invasiveness worldwide, we argue that all three cichlid species are unlikely to spread and persist permanently beyond the thermally influenced range of the Gillbach river system. However, convict cichlids from the Gillbach are known to host both native and non-native fish parasites and thus, non-native cichlids may constitute threats to the native fish fauna. We therefore strongly recommend continuous monitoring of the Gillbach and similar systems