Abstract
Neurofibromatosis type 1 (NF1) is a common dominant inherited disorder with highly variable expressivity. Genetic testing for this condition has been more available the last decade. Here we present a case report of a NF1 family including seven affected family members, some of them with a very severe phenotype. When searching for a causative mutation in the NF1 gene, no mutation was found at DNA level. However, a misspliced transcript including a subsequence of intron 3 appeared when screening RNA. The underlying cause at DNA level was determined to be a deep intronic variant (c.288+1137C>T). This intronic point mutation creates a new splice site causing the insertion of a cryptic exon (r.288_289ins288+1018_1135), leading to reading frameshift at the protein level. Deep intronic mutations introducing a cryptic exon are known to be a cause of NF1, and we reviewed the literature to evaluate how common this mutation is in NF1 syndrome. We found 20 different deep intronic NF1 splice mutations, including the one found in the present study. In conclusion, this case illustrates the value of RNA analysis to detect the cause of genetic diseases, and we decided to use RNA based mutation screening as standard procedure for NF1 genetic testing in our laboratory.
Highlights
Neurofibromatosis type 1 (NF1), called von Recklinghausen disease (OMIM # 162200), is one of the most common dominant inherited disorders; the worldwide incidence is 1/3500 [1,2,3]
Genetic modifiers that lie outside the NF1 gene appear to account for a large fraction of the symptomatic variability seen in NF1 [3,8]
No pathogenic NF1 mutation was initially detected in genomic DNA from two of the affected siblings
Summary
Neurofibromatosis type 1 (NF1), called von Recklinghausen disease (OMIM # 162200), is one of the most common dominant inherited disorders; the worldwide incidence is 1/3500 [1,2,3]. Individuals with NF1 have increased risk to develop malignant tumours, among which malignant peripheral nerve sheath tumours (MPNSTs) are the most severe. The clinical manifestations of NF1 shows highly variable expression, i.e. the severity of disease varies among affected individuals within the same family and from one family to another [2]. Obvious genotype-phenotype correlations are not common in NF1 [1,4,5]. Two clear clinically important genotype-phenotype correlations are revealed so far; one concerns patients with severe forms of NF1 that carry large deletions encompassing the entire NF1 gene [3,6,7] and the other concerns patients carrying small mutations such as a 3-bp inframe deletion of the NF1 gene [8]. Genetic modifiers that lie outside the NF1 gene appear to account for a large fraction of the symptomatic variability seen in NF1 [3,8]
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