Neurofibromatosis type I: mutation spectrum of NF1 in spanish patients

Abstract

Neurofibromatosis type I (NF1) is one of the most common genetic disorders in humans. NF1, a tumor predisposition syndrome, is caused by heterozygous pathogenic variants in the NF1 gene. Molecular genetic testing of NF1 is complex, especially because of the presence of a high number of partial pseudogenes, some of them with a high percentage of sequence identity. In this study, we have analyzed the largest cohort of NF1 Spanish patients (150 unrelated individuals suspected of having NF1 and 53 relatives, making a total of 203 individuals). Mutation analysis of the entire coding region was performed in all unrelated index patients. Additionally, the Multiplex Ligation-dependent Probe Amplification (MLPA) test of the NF1 gene and SPRED1 gene analysis (sequencing and MLPA test) was performed in some of the negative patients for NF1 point mutations. When fulfilling the National Institutes of Health (NIH) criterion for the clinical diagnosis of NF1, the detection rate was 79%. Among the 80 genetically confirmed NF1 probands, we detected 69 different pathogenic variants. Two mutations (3%) were gross deletions of the whole gene, the remaining 78 mutations (97%) were small changes spread among all NF1 exons. Among these 69 different mutations detected, 42 mutations were described elsewhere, and 27 mutations were novel mutations. When segregation was studied, 67% of mutations resulted de novo variants. No genetic mosaicism was detected on patients' parents.

Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation‐dependent probe amplification and genotype–phenotype correlation in 138 Turkish patients

“…Seventy‐three distinct intragenic NF1 variants found in the current study have a similar distribution pattern found in previous studies thus confirming the absence of hot‐spot regions (Barrea et al., 2018; Bonatti et al., 2017; Kang et al., 2020; Terzi et al., 2007). According to previous studies, most of the germline pathogenic NF1 variants appear to cause truncation of the gene product, often by altering mRNA splicing (Friedman, 1993; Palma Milla et al., 2018). Similarly, the majority of patients with intragenic NF1 variants in our cohort had truncating (72.6%), and the remaining 27.3% had nontruncating alleles.…”

“…Large NF1 deletions have frequently been associated with a severe phenotype, including dysmorphic facial features, overgrowth/tall‐for‐age stature, and cognitive developmental delay. (Kehrer‐Sawatzki et al., 2017; Palma Milla et al., 2018). Consistent with the literature, six out of seven patients with large deletions had delay in cognitive development.…”

“…Consistent with the literature, six out of seven patients with large deletions had delay in cognitive development. Patients with large NF1 deletions also display earlier onset of cutaneous neurofibromas, increased numbers of subcutaneous, plexiform and spinal neurofibromas, as well as an increased lifetime risk of MPNSTs (Kehrer‐Sawatzki et al., 2017; Palma Milla et al., 2018). However, neurofibroma development was not observed in seven patients with large NF1 deletions presented here.…”

“…Only a few genotype–phenotype correlations in NF1 have been reported to date. Large NF1 deletions have been associated with a severe NF1 phenotype (Kehrer‐Sawatzki et al., 2017; Palma Milla et al., 2018). The second genotype–phenotype correlation in NF1 involves the c.2970_2972delAAT (p.Met992del) variant, associated with a relatively mild phenotype (Kehrer‐Sawatzki et al., 2017).…”

How to Distinguish Solitary Neurofibroma From Neurofibromatosis Type 1

“…The reason has not been established. Therefore, even if the gene test revealed a false-negative result, it could not be used to rule out NF1 diagnosis, which may lead to a misdiagnosis 6 . Therefore, we propose a method to confirm the diagnosis.…”