Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Abstract

We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

Clinical spectrum of individuals with pathogenic N F1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype–phenotype study in neurofibromatosis type 1

“…In this study, we report an additional NF1 variant, p.Met1149Val, associated specifically with a mild form of NF1 without externally visible plexiform or symptomatic spinal neurofibromas, symptomatic OPGs or malignant neoplasms similar to the phenotypes associated with variants at p.Arg1809 and p.Met992del (Koczkowska et al, ; Pinna et al, ; Rojnueangnit et al, ; Upadhyaya et al, ). As only six probands were identified so far with either the p.Met1149Ile or p.Met1149Thr (Table S7), even larger datasets, as well as follow‐up of individuals enrolled in the current study, are required to further refine a mild phenotype associated with the other substitutions at p.Met1149.…”

“…So far, only two specific NF1 pathogenic variants have been associated with a statistically significant increased prevalence of Noonan‐like features compared with “classic” NF1‐affected cohorts, i.e., p.Arg1809 and p.Met992del, both located outside the GRD (Koczkowska et al, ; Pinna et al, ; Rojnueangnit et al, ; Upadhyaya et al, ). Here, we report that NF1 pathogenic missense variants at p.Met1149, p.Arg1276, and p.Lys1423 also are associated with this distinct phenotype (all p < .0001, significant at FDR of 0.01 after B‐H correction), with no pathogenic variants in other NS genes detected (Tables S6, S8, S10, S12, S20, and S21).…”

“…Comprehensive NF1 molecular analysis, interpretation of variant pathogenicity and collection of clinical data (see details in Supporting Information Methods) was performed as previously described (Koczkowska et al, ; Koczkowska et al, ; Messiaen et al, ; Richards et al, ; Rojnueangnit et al, ). Two‐tailed Fisher's exact test with p < .05 considered as statistically significant was applied.…”

“…Indeed, only six true nontruncating hotspots, each with a prevalence ≥0.4%, were found in the UAB cohort, i.e., missense variants at codons 844‐848, 1149, 1276, 1423, and 1809 and a single amino acid deletion p.Met992del (Figure ). To date, genotype–phenotype associations affecting pathogenic missense variants at NF1 codons 1809 and 844‐848 and p.Met992del have been reported, representing approximately 1.2, 0.8, and 0.9% of unrelated probands, respectively (Koczkowska et al, ; Koczkowska et al, ; Pinna et al, ; Rojnueangnit et al, ; Upadhyaya et al, ). Increased efforts towards the identification of additional clinically relevant genotype–phenotype correlations are needed.…”

Five novel NF1 gene pathogenic variants in 10 different Chinese families with neurofibromatosis type 1

“…Neurofibromatosis type 1 (NF1) is characterized by obvious age‐related penetrance and wide clinical variability, but almost all adults with NF1 present with cutaneous and/or subcutaneous neurofibromas (Koczkowska et al, ; Uusitalo et al, ). Multiple osseous lesions including CPT, tibial dysplasia, scoliosis, and decreased bone mineral density (BMD) are related to neurofibromatosis type 1 (Stevenson et al, ).…”