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    • The present study quantifies the level of reassurance

    2018-11-05

    The present study quantifies the level of reassurance a parent may have on diagnostic testing that their child does not have NF1 if there is no sequence variant in NF1 or SPRED1 when their child has 6 or more CAL. Around 25% of children tested did not have an identifiable mutation. Using a Bayesian calculation and assuming 95.8% sensitivity for testing in an isolated case fulfilling NIH criteria there would still be a 1 in 9 chance that their child had NF1 (Table 5). However, this rises to 1 in 6 if only DNA testing was carried out. DNA testing would also increase the likelihood that the parents would be given an uncertain result with the VUS rate rising from 4.2% to 8.6% because of failure to be able to classify missense and splicing variants outside the consensus splicing region as functional. We also found a significant rate of 8.5% (1 in 12) for SPRED1 mutations. These were previously shown to be more frequent in familial CAL than in sporadic cases with 19% of familial CAL due to SPRED1 (Messiaen et al., 2009). The present study has defined a very high sensitivity for a mutation screening approach incorporating RNA testing in identifying a mutation in NF1 affected individuals meeting NIH criteria with at least one non-pigmentary criterion. This enables a great deal of reassurance to unaffected parents of children with >5 CAL as the likelihood of their child having constitutional NF1 drops from over 60% to as little as 11%. DNA based testing alone classifies fewer cases as having definite NF1 and a negative screen purchase GSK2656157 a 1 in 6 chance the child will still have NF1. Finally, among the very small number without an identifiable mutation who do meet NIH criteria it remains possible that a rare further second gene may be responsible for a condition which also predisposes to DNET.
    Author Contributions Conception, study design: DGE, SMH, AJW; patient data contribution: DGE, SMH, MP-S, GV, AD, EB-W, SG, EH, JE; RNA analysis and MLPA: EM, NB, AJW; data analysis DGE, AJW, WN, VS-K; Interpretation: DGE, AJW, WN, SMH; manuscript drafting all; approval of final version: all.
    Acknowledgements
    Introduction Obstructive sleep apnea (OSA) is a debilitating, chronic multisystem sleep disorder that arises from recurrent partial or complete pharyngeal obstruction during sleep (Lévy et al., 2015; Malhotra et al., 2015). It has been proposed to have an important, if not fully understood, bidirectional relationship with several major neurological disorders (Lévy et al., 2015; Rosenzweig et al., 2015; Rosenzweig et al., 2014). A close association of OSA with early onset of cognitive decline, by as much as a decade, has been reported, whilst a growing body of clinical and animal work advocates that OSA should be recognized as one of the rare modifiable risks for Alzheimer\'s dementia (Rosenzweig et al., 2015; Osorio et al., 2015; Yaffe et al., 2014). In addition, treatment with Continuous Positive Airway Pressure (CPAP), the main treatment for OSA, has been also variably shown to halt the onset, decelerate the progression, or offer a better prognosis in patients with co-morbid dementia, epilepsy and stroke (Osorio et al., 2015; Yaffe et al., 2014; Campos-Rodriguez et al., 2014; Pornsriniyom et al., 2014; McMillan et al., 2015). Numerous clinical studies over the years have demonstrated changes in the central nervous system (CNS) of patients with OSA, including altered resting cerebral blood flow pattern (Baril et al., 2015) with hypoperfusion during the awake states (Joo et al., 2007), changes in the electroencephalogram (EEG) and aberrant cortical excitability (Morisson et al., 1998, 2001; Dingli et al., 2002) and changes in both white and gray matter (Zimmerman and Aloia, 2006; Torelli et al., 2011; Kumar et al., 2014; Morrell and Glasser, 2011; Macey et al., 2008). These studies have largely also suggested a putative neurocircuitry fingerprint at which core lies the disconnection of the frontal regions (O\'Donoghue et al., 2012) and the disruption of the (cerebello)-thalamocortical oscillator with involvement of the hippocampal formation (Rosenzweig et al., 2013a, 2014; Torelli et al., 2011; Yaouhi et al., 2009).