Ultra-deep amplicon sequencing indicates absence of low-grade mosaicism with normal cells in patients with type-1 NF1 deletions

Summerer, Anna; Schäfer, Eleonora; Mautner, Victor‐Felix; Messiaen, Ludwine; Cooper, David Neil; Kehrer‐Sawatzki, Hildegard

doi:10.1007/s00439-018-1961-5

Cited by 14 publications

(18 citation statements)

References 51 publications

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“…Hence, we cannot exclude somatic mosaicism with normal cells not harbouring the NF1 microdeletion in patient 1261 which would explain the high FSIQ and the absence of developmental delay in this patient. However, somatic mosaicism with normal cells not harbouring the NF1 microdeletion is very rare in patients with type-1 NF1 deletions [12,13]. Table 5 FSIQ in patients with NF1 microdeletions analysed by Descheemaeker et al [22], Mautner et al [18], Ottenhoff et al [23] and in the present study Descheemaeker et al [22] Mautner et al [18] Ottenhoff et al [23] This study [22].…”

Section: Developmental Delaysupporting

confidence: 50%

Section: Resultsmentioning

confidence: 99%

“…Most frequent are type-1 NF1 microdeletions which encompass 1.4 Mb and include 14 protein-coding genes as well as four microRNA genes [ 9 – 11 ]. Type-1 deletions account for 70–80% of all large NF1 deletions and usually occur as germline deletions that are present in all cells of the affected patients [ 12 , 13 ]. Less frequent than type-1 NF1 deletions are type-2, type-3 and atypical NF1 deletions that are distinguishable by their size and breakpoint location, by the number of genes located within the deletion region and the frequency of mosaicism with normal cells without the NF1 microdeletion [reviewed by 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Clinical characterization of children and adolescents with NF1 microdeletions

et al. 2020

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Purpose An estimated 5–11% of patients with neurofibromatosis type 1 (NF1) harbour NF1 microdeletions encompassing the NF1 gene and its flanking regions. The purpose of this study was to evaluate the clinical phenotype in children and adolescents with NF1 microdeletions. Methods We retrospectively analysed 30 children and adolescents with NF1 microdeletions pertaining to externally visible neurofibromas. The internal tumour load was determined by volumetry of whole-body magnetic resonance imaging (MRI) in 20 children and adolescents with NF1 microdeletions. Furthermore, the prevalence of global developmental delay, autism spectrum disorder and attention deficit hyperactivity disorder (ADHD) were evaluated. Results Children and adolescents with NF1 microdeletions had significantly more often cutaneous, subcutaneous and externally visible plexiform neurofibromas than age-matched patients with intragenic NF1 mutations. Internal neurofibromas were detected in all 20 children and adolescents with NF1 microdeletions analysed by whole-body MRI. By contrast, only 17 (61%) of 28 age-matched NF1 patients without microdeletions had internal tumours. The total internal tumour load was significantly higher in NF1 microdeletion patients than in NF1 patients without microdeletions. Global developmental delay was observed in 28 (93%) of 30 children with NF1 microdeletions investigated. The mean full-scale intelligence quotient in our patient group was 77.7 which is significantly lower than that of patients with intragenic NF1 mutations. ADHD was diagnosed in 15 (88%) of 17 children and adolescents with NF1 microdeletion. Furthermore, 17 (71%) of the 24 patients investigated had T-scores ≥ 60 up to 75, indicative of mild to moderate autistic symptoms, which are consequently significantly more frequent in patients with NF1 microdeletions than in the general NF1 population. Also, the mean total T-score was significantly higher in patients with NF1 microdeletions than in the general NF1 population. Conclusion Our findings indicate that already at a very young age, NF1 microdeletions patients frequently exhibit a severe disease manifestation which requires specialized long-term clinical care.

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Section: Developmental Delaysupporting

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical characterization of children and adolescents with NF1 microdeletions

et al. 2020

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“…The limitation of WES and MLPA might make some NF1 variants undetected. For example, microdeletions, inversion, translocation or abnormal karyotype might interfere with NF1 [12, 38–40]. In addition, non-coding variants from the regulating area of NF1 could be among the undetected genetic lesions.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of NF1 and non-NF1 congenital pseudarthrosis of the tibia based on germline NF1 variants: genetic and clinical analysis of 75 patients

Zhu

Zheng

Liu

et al. 2019

Orphanet J Rare Dis

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Background Congenital pseudarthrosis of the tibia (CPT) is a rare disease. Some patients present neurofibromatosis type 1 (NF1), while some others do not manifest NF1 (non-NF1). The etiology of CPT, particularly non-NF1 CPT, is not well understood. Here we screened germline variants of 75 CPT cases, including 55 NF1 and 20 non-NF1. Clinical data were classified and analyzed based on NF1 gene variations to investigate the genotype-phenotype relations of the two types of patients. Results Using whole-exome sequencing and Multiplex Ligation-Dependent Probe Amplification, 44 out of 55 NF1 CPT patients (80.0%) were identified as carrying pathogenic variants of the NF1 gene. Twenty-five variants were novel; 53.5% of variants were de novo, and a higher proportion of their carriers presented bone fractures compared to inherited variant carriers. No NF1 pathogenic variants were found in all 20 non-NF1 patients. Clinical features comparing NF1 CPT to non-NF1 CPT did not show significant differences in bowing or fracture onset, lateralization, tissue pathogenical results, abnormality of the proximal tibial epiphysis, and follow-up tibial union after surgery. A considerably higher proportion of non-NF1 patients have cystic lesion (Crawford type III) and used braces after surgery. Conclusions We analyzed a large cohort of non-NF1 and NF1 CPT patients and provided a new perspective for genotype-phenotype features related to germline NF1 variants. Non-NF1 CPT in general had similar clinical features of the tibia as NF1 CPT. Germline NF1 pathogenic variants could differentiate NF1 from non-NF1 CPT but could not explain the CPT heterogeneity of NF1 patients. Our results suggested that non-NF1 CPT was probably not caused by germline NF1 pathogenic variants. In addition to NF1, other genetic variants could also contribute to CPT pathogenesis. Our findings would facilitate the interpretation of NF1 pathogenic variants in CPT genetic counseling.

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“…Type-1 deletions have a size of 1.4Mb and include 14 protein-coding genes as well as four microRNA genes [9][10][11]. These deletions usually occur as germline mutations, which are present in all cells of affected patients [12,13]. Less frequently identified are so-called atypical deletions, distinguishable by size, breakpoint location, number of affected genes and frequency of mosaicism [4].…”

Section: Introductionmentioning

confidence: 99%

Genotype-phenotype correlation in neurofibromatosis type-1: NF1 whole gene deletions lead to high tumor-burden and increased tumor-growth

et al. 2021

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Neurofibromatosis type-1 (NF1) patients suffer from cutaneous and subcutaneous neurofibromas (CNF) and large plexiform neurofibromas (PNF). Whole gene deletions of the NF1 gene can cause a more severe phenotype compared to smaller intragenic changes. Two distinct groups of NF1 whole gene deletions are type-1 deletions and atypical deletions. Our aim was to assess volumes and averaged annual growth-rates of CNF and PNF in patients with NF1 whole gene deletions and to compare these with NF1 patients without large deletions of the NF1 gene. We retrospectively evaluated 140 whole-body MR examinations of 38 patients with NF1 whole gene deletions (type-1 group: n = 27/atypical group n = 11) and an age- and sex matched collective of 38 NF1-patients. Age-dependent subgroups were created (0–18 vs >18 years). Sixty-four patients received follow-up MRI examinations (NF1whole gene deletion n = 32/control group n = 32). Whole-body tumor-volumes were semi-automatically assessed (MedX, V3.42). Tumor volumes and averaged annual growth-rates were compared. Median tumor-burden was significantly higher in the type-1 group (418ml; IQR 77 – 950ml, p = 0.012) but not in the atypical group (356ml;IQR 140–1190ml, p = 0.099) when compared to the controls (49ml; IQR 11–691ml). Averaged annual growth rates were significantly higher in both the type-1 group (14%/year; IQR 45–36%/year, p = 0.004) and atypical group (11%/year; IQR 5–23%/year, p = 0.014) compared to the controls (4%/year; IQR1–8%/year). Averaged annual growth rates were significantly higher in pediatric patients with type-1 deletions (21%/year) compared with adult patients (8%/year, p = 0.014) and also compared with pediatric patients without large deletions of the NF1 gene (3.3%/year, p = 0.0015). NF1 whole gene deletions cause a more severe phenotype of NF1 with higher tumor burden and higher growth-rates compared to NF1 patients without large deletions of the NF1 gene. In particular, pediatric patients with type-1 deletions display a pronounced tumor growth.

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Ultra-deep amplicon sequencing indicates absence of low-grade mosaicism with normal cells in patients with type-1 NF1 deletions

Cited by 14 publications

References 51 publications

Clinical characterization of children and adolescents with NF1 microdeletions

Clinical characterization of children and adolescents with NF1 microdeletions

Identification and characterization of NF1 and non-NF1 congenital pseudarthrosis of the tibia based on germline NF1 variants: genetic and clinical analysis of 75 patients

Genotype-phenotype correlation in neurofibromatosis type-1: NF1 whole gene deletions lead to high tumor-burden and increased tumor-growth

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