Reanalysis of Whole Exome and Genome Data Leads to New Diagnoses in Children with Intellectual Disability and Developmental Delay

Truncating mutations including frameshift mutations and nonsense mutations contribute to ~45% of all mutations leading to NF1. However, the extent to which specific mechanisms are involved in causing these mutations has not been well explored yet. Here, we analyzed the frequency and characteristics of 1,924 and 1,731 NF1 individuals carrying frameshift and nonsense mutations respectively out of a total number of ~8,100 unrelated NF1 mutationpositive probands from the University of Alabama at Birmingham Medical Genomics Laboratory and inferred their likely mutational mechanisms. Interestingly, eight frameshift mutation hotspots were identified, which were associated with non-B DNA structures and short tandem repeats. On the other hand, 18 nonsense mutation hotspots were identified, which all occurred at CpG dinucleotides. Furthermore, it is believed that a termination codon must reside further than 5055 nucleotides upstream of the splice donor of the penultimate exon, for nonsense-mediated mRNA be able to decay the transcripts. However, no constitutional truncating mutations beyond c.8154 were found in our cohort, nor have been described in other disease-associated datasets, which is 160 nucleotides before the exon 57 end, suggesting truncating mutations downstream of c.8154 may not result in an NF1 phenotype.