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    • Ion Channel Compound Library Seventy one individuals aged wi

    2018-10-23

    Seventy one individuals aged <20 with 6+ CAL and no non-pigmentary NF1 criterion had an RNA sample assessed (Table 5). 44/71 (62%) had a clearly deleterious NF1 mutation, this included six with missense variants that were shown to have arisen de novo (c.2329T>C p.(Trp777Arg); c.3610C>G p.(Arg1204GIy); c.4016T>G (p.Leu1339Arg); c.4267A>G p.(Lys1423Glu); c.5425C>T p.(Arg1809Cys); c.6950T>C p.(Leu2317Pro); and also an in frame Ion Channel Compound Library not present in the parents lymphocyte DNAs (c.3327_3329del p.(Leu1109del)). All of these variants were also predicted to be deleterious on in silico analysis and were in conserved amino-acid residues across species and the latter four missense variants also excluded in both parents. There were also: fifteen nonsense, ten splice site/splicing variants (including c.1260+1604A>G also seen in Table 3) with three only classified by RNA, ten frameshift and one deletion of exon2 and one whole gene deletion (type 1). One nonsense mutation was detected as a mosaic (estimated 18% mutant cellular fraction) in lymphocyte RNA in an individual aged 19years at assessment who had 6 faint CAL (c.5839C>T p.(Arg1947Ter)). A further three individuals had missense mutations that had in silico evidence and conservation across species to predict they were disease causing (c.1658A>G p.(His553Arg); c.5425C>T p.(Arg1809Cys); c.6554C>G p.(Thr2185Arg)) the former two also had evidence from a previous patients that they had arisen de novo. There were six patients from this cohort with predicted loss of function SPRED1 mutations (8.4%) one was proven de novo (c.190C>T p.(Arg64Ter)) and four further mutations were assumed to be de novo as the parents had no features (c.177dupT p.(Ile60TyrfsTer18); c.360delA p.(Ile120MetfsTer32); c.1048_1060del13 p.(Gly350MetfsTer52); c.304dupA p.(Thr102AsnfsTer7)) and a further mutation was found to have been inherited from a mother who on closer inspection was found to have 4 CAL (c.482_483delCA p.(Thr161SerfsTer5)). Seventeen individuals (24%) had no mutation identified in either NF1 or SPRED1 and one had a missense variant c.4768C>T (p.Arg1590Trp) in NF1 that was inherited from his father without CAL and assumed to be unrelated to his CAL. Since 2013 we have screened one hundred and thirty two samples from patients that did not meet NIH criteria where no NF1 mutation or variant was identified following comprehensive RNA level and MLPA copy number analysis.
    Discussion The present study has shown a very high detection rate for NF1 mutations in classically affected individuals meeting NIH criteria. There was no difference in detection rates between the familial and de novo group although two patients with de novo NF1 including one with an affected child had mosaicism detected in lymphocyte RNA. This study would therefore suggest that levels of mosaicism undetectable in RNA/DNA are unlikely to cause classical NF1. Mosaicism is nonetheless well documented as the cause of segmental NF1 where identical NF1 mutations can be detected in melanocyte cultures from anatomically separate CAL (Maertens et al., 2007). Nonetheless mosaic large deletions that are harder to detect by MLPA (as this will usually only detect down to around 20% level) have been shown to cause an occasional generalised case (Messiaen et al., 2011). However, both cases reported in the series with large deletions were present at 50% or greater level (25% mutant allele fraction) and should therefore have been identified in our current study. It is nonetheless possible that the more severe phenotype associated with whole gene deletions may cause generalised disease with even lower levels of mosaicism, whereas this would be less likely for point mutations at below 10% mutant allele fraction. A previous RNA analysis identified 64/67 (95%) of mutations in clearly affected NF1 individuals (Messiaen et al., 2000). This study was based on much smaller numbers: 29/29 with familial and 35/38 sporadic had mutations identified, but was not able to differentiate statistically between inherited and sporadic cases (p=0.25).