Revealing the Complexity of a Monogenic Disease: Rett Syndrome Exome Sequencing

Medical Genetics, University of Siena, Siena, Italy.
PLoS ONE (Impact Factor: 3.23). 02/2013; 8(2):e56599. DOI: 10.1371/journal.pone.0056599
Source: PubMed


Rett syndrome (OMIM#312750) is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene /X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same OMIM*300005) mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome), while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant). In addition to the mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

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    • "Our group and other laboratories have reported enhanced OS markers levels in plasma and erythrocytes from patients with RTT, thus suggesting the presence of a systemic OS in the disease. However, to date, it is unclear not only why, but also when, and where this OS derangement may occur [19] [20] [21] [22] [23] [24] [25] [26]. "
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    ABSTRACT: Evidence of oxidative stress has been reported in the blood of patients with Rett syndrome (RTT), a neurodevelopmental disorder mainly caused by mutations in the gene encoding the Methyl-CpG-binding protein 2. Little is known regarding the redox status in RTT cellular systems and its relationship with the morphological phenotype. In RTT patients (n = 16) we investigated four different oxidative stress markers,F 2-Isoprostanes (F2-IsoPs), F4-Neuroprostanes (F4-NeuroPs), nonprotein bound iron (NPBI), and (4-HNE PAs), and glutathione in one of the most accessible cells, that is, skin fibroblasts, and searched for possible changes in cellular/intracellular structure and qualitative modifications of synthesized collagen. Significantly increasedF 4-NeuroPs (12-folds), F2-IsoPs (7.5-folds) NPBI (2.3-folds), 4-HNE PAs (1.48-folds), and GSSG (1.44-folds) were detected, with significantly decreased GSH (−43.6%) and GSH/GSSG ratio (−3.05 folds). A marked dilation of the rough endoplasmic reticulum cisternae, associated with several cytoplasmic multilamellar bodies, was detectable in RTT fibroblasts. Colocalization of collagen I and collagen III, as well as the percentage of type I collagen as derived by semiquantitative immunofluorescence staining analyses, appears to be significantly reduced in RTT cells. Our findings indicate the presence of a redox imbalance and previously unrecognized morphological skin fibroblast abnormalities in RTT patients.
    Oxidative medicine and cellular longevity 05/2014; 2014. DOI:10.1155/2014/195935 · 3.36 Impact Factor
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    • "Each strain of laboratory mouse represents a distinct genetic background that is known to significantly alter baseline behaviors (Crawley et al., 1997; Holmes et al., 2002; Bothe et al., 2004; Moy et al., 2007), and several studies have demonstrated that the genetic background has a significant impact on multiple behavioral responses, including ASD-like traits, in mouse models of Fragile X syndrome, for example (Dobkin et al., 2000; Errijgers et al., 2008; Baker et al., 2010; Pietropaolo et al., 2011; Spencer et al., 2011). When such a change is identified, it can lead to identifying modifier loci that modulate phenotypes, as has recently been done in models for Rett syndrome (Buchovecky et al., 2013; Grillo et al., 2013), leading to a better understanding of pathophysiology and opportunities for therapeutics. "
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    ABSTRACT: Haploinsufficiency of SHANK3, caused by chromosomal abnormalities or mutations that disrupt one copy of the gene, leads to a neurodevelopmental syndrome called Phelan-McDermid Syndrome that can include absent or delayed speech, intellectual disability, neurological changes, and autism spectrum disorders. The SHANK3 protein forms a key structural part of the post-synaptic density. We previously generated and characterized mice with a targeted disruption of Shank3 in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in Shank3 heterozygous mice. Changes in phenotype due to a mutation at a single locus are quite frequently modulated by other loci, most dramatically when the entire genetic background is changed. In mice, each strain of laboratory mouse represents a distinct genetic background and alterations in phenotype due to gene knockout or transgenesis are frequently different across strains, which can lead to the identification of important modifier loci. We have investigated the effect of genetic background on phenotypes of Shank3-heterozygous, knock-out and wild-type mice, using C57BL/6, 129SVE, and FVB/Ntac strain backgrounds. We focused on observable behaviors with the goal of carrying out subsequent analyses to identify modifier loci. Surprisingly, there were very modest strain effects over a large battery of analyses. These results indicate that behavioral phenotypes associated with Shank3 haploinsufficiency are largely strain independent.
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    • "With recent declines in price and increasing numbers of Clinical Laboratory Improvement Amendments (CLIA)-approved laboratories offering the testing clinically, WES has already begun to revolutionize genetic testing (Jamal et al., 2013). Thus far, WES has successfully identified underlying mutations for rare, monogenic syndromes (Choi et al., 2009; Ng et al., 2010), unveiled complex features of more common monogenic disorders (Grillo et al., 2013), and accelerated diagnostic discoveries (Worthey et al., 2011). "
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    ABSTRACT: Whole exome sequencing (WES) uses next generation sequencing technology to provide information on nearly all functional, protein-coding regions in an individual's genome. Due to the vast amount of information and incidental findings that can be generated from this technology, patient preferences must be investigated to help clinicians consent and return results to patients. Patients (n = 19) who were previously clinically diagnosed with Lynch syndrome, but received uninformative negative Lynch syndrome genetic results through traditional molecular testing methods participated in semi-structured interviews after WES testing but before return of results to explore their views of WES and preferences for return of results. Analyses of interview results found that nearly all participants believed that the benefits of receiving all possible results generated from WES outweighed the undesirable effects. The majority of participants conveyed that relative to coping with a cancer diagnosis, information generated from WES would be manageable. Importantly, participants' experience with Lynch syndrome influenced their notions of genetic determinism, tolerance for uncertain results, and family communication plans. Participants would prefer to receive WES results in person from a genetic counselor or medical geneticist so that an expert could help explain the meaning and implications of the potentially large quantity and range of complicated results. These results underscore the need to study various populations with regard to the clinical use of WES in order to effectively and empathetically communicate the possible implications of this new technology and return results.
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