X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern

Sedimentary facies of a glacially influenced continental succession in the Pennsylvanian Jericho Formation, Galilee Basin, Australia

Recent work on the Late Palaeozoic Ice Age in eastern Australia has shown the Joe Joe Group in the eastern Galilee Basin, Queensland, to be of critical importance as it is one of few records of Pennsylvanian glacial activity outside South America. This paper presents detailed sedimentological data, from which the Late Palaeozoic environment of the region is reconstructed and which, consequently, allows for robust comment on the broader Gondwanan glaciation. The Jericho Formation, in the lower Joe Joe Group, was deposited in an active extensional basin in lacustrine to fluvial environments, during the mid-Namurian to early Stephanian. The region experienced a cool climate during this time, and polythermal mountain or valley-type glaciers periodically advanced into the area from highlands to the north-east. The Jericho Formation preserves a suite of proglacial to terminal glacial facies that is characterized by massive and stratified diamictites deposited from debris flows, massive and horizontally laminated conglomerates and sandstones deposited from hyperconcentrated density flows, laminated siltstones with outsized clasts and interlaminated siltstone/ conglomerate deposited through ice-rafting into lakes, and sedimentary dykes and breccias deposited through overpressurization of groundwater beneath permafrost. Non-glacial facies are dominated by fluvial sandstones and lacustrine/overbank siltstones. The glacigenic rocks of the Jericho Formation are confined to discrete packages, recording three separate glacial advances during the latest Namurian to late Westphalian. This arrangement is consistent with the temporal distribution of glacigenic rocks from around the remainder of Australia and Gondwana, which supports the theory that glacial deposits occurred in discrete intervals. The Joe Joe Group is a key succession in the world in this context as, at this time, eastern Australia provides the only unequivocal evidence of a Namurian/Westphalian glaciation outside South America. The continuous record of sedimentation through the Pennsylvanian and Early Permian is indicative of significant warming between glacial intervals, which is difficult to reconcile with the development of long-lived, cold-based ice sheets across the supercontinent. © 2007 The Authors. Journal compilatio

The utility of Next Generation Sequencing for molecular diagnostics in Rett syndrome

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that almost exclusively affects girls and is totally disabling. Three genes have been identified that cause RTT: MECP2, CDKL5 and FOXG1. However, the etiology of some of RTT patients still remains unknown. Recently, next generation sequencing (NGS) has promoted genetic diagnoses because of the quickness and affordability of the method. To evaluate the usefulness of NGS in genetic diagnosis, we present the genetic study of RTT-like patients using different techniques based on this technology. We studied 1577 patients with RTT-like clinical diagnoses and reviewed patients who were previously studied and thought to have RTT genes by Sanger sequencing. Genetically, 477 of 1577 patients with a RTT-like suspicion have been diagnosed. Positive results were found in 30% by Sanger sequencing, 23% with a custom panel, 24% with a commercial panel and 32% with whole exome sequencing. A genetic study using NGS allows the study of a larger number of genes associated with RTT-like symptoms simultaneously, providing genetic study of a wider group of patients as well as significantly reducing the response time and cost of the study

Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations