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

Koczkowska, Magdalena; Callens, Tom; Chen, Yunjia; Gomes, Alicia; Hicks, Alesha D.; Sharp, Angela; Johns, Eric; Uhas, Kim; Armstrong, Linlea; Bosanko, Katherine A.; Babovic‐Vuksanovic, Dusica; Baker, Laura; Basel, Donald; Bengala, Mario; Bennett, James T.; Chambers, Chelsea; Clarkson, L. Kate; Clementi, Maurizio; Cortés, Fanny; Cunningham, Mitch; D’Agostino, Maria Daniela; Delatycki, Martin B.; Digilio, María Cristina; Dosa, Laura; Susan, Esposito; Fox, Stéphanie; Freckmann, Mary Louise; Fauth, Christine; Giugliano, Teresa; Giustini, Sandra; Goetsch, Allison L.; Goldberg, Yael; Greenwood, Robert; Griffis, Cristin; Gripp, Karen W.; Gupta, Punita; Haan, Eric; Hachen, Rachel K.; Haygarth, Tamara L.; Hernández-Chico, Concepción; Hodge, Katelyn; Hopkin, Robert J.; Hudgins, Louanne; Janssens, Sandra; Keller, Kory; Kelly‐Mancuso, Geraldine; Kochhar, Aaina; Korf, Bruce R.; Lewis, Andrea M.; Liebelt, Jan; Lichty, Angie; Listernick, Robert; Lyons, Michael J.; Maystadt, Isabelle; Ojeda, Mayra Martinez; McDougall, Carey; McGregor, Lesley; Melis, Daniela; Mendelsohn, Nancy J.; Nowaczyk, Małgorzata J.M.; Ortenberg, June; Panzer, Karin; Pappas, John; Pierpont, Mary Ella M; Piluso, Giulio; Pinna, Valentina; Pivnick, Enikö K.; Pond, Dinel; Powell, Cynthia M.; Rogers, Caleb; Shahar, Noa Ruhrman; Rutledge, S. Lane; Saletti, Veronica; Sandaradura, Sarah A.; Santoro, Claudia; Schatz, Ulrich; Schreiber, Allison; Scott, Daryl A.; Sellars, Elizabeth A.; Sheffer, Ruth; Siqveland, Elizabeth; Slopis, John M.; Smith, Rosemarie; Spalice, Alberto; Stockton, David W.; Streff, Haley; Theos, Amy; Tomlinson, Gail E.; Tran, Grace; Trapane, Pamela; Trevisson, Eva; Ullrich, Nicole J.; Ende, Jenneke van den; Vergano, Samantha A. Schrier; Wallace, Stephanie E; Wangler, Michael F.; Weaver, David D.; Yohay, Kaleb; Zackai, Elaine H.; Zonana, Jonathan; Zurcher, Vickie; Claes, Kathleen; Eoli, Marica; Martín, Yolanda; Wimmer, Katharina; Luca, Alessandro De; Legius, Eric; Messiaen, Ludwine

doi:10.1002/humu.23929

Cited by 106 publications

(108 citation statements)

References 49 publications

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“…This is very hard to achieve, since a recent study using the largest NF1 gene variant database to date (8000 individuals) showed that a combination of the six most common recurrent missense or in-frame mutational hotspots (i.e., p.844-848, p.Met992del, p.Met1149, p.Arg1276, p.Lys1423, and p.Arg1809) represents only 4.8% of unrelated probands. 45 There are several clinical implications of our findings. First of all, we provide a robust confirmation that the chromosomal microdeletion genotype is associated with a lower cognitive ability compared with intragenic NF1 genotypes.…”

Section: Discussionmentioning

confidence: 78%

“…Nevertheless, intragenic genotype-phenotype correlations concerning a single or a few neighboring amino acids (i.e., p.844-848, p.Met992del, p.Met1149, p.Arg1276, p.Lys1423, and p.Arg1809) have been identified in the context of somatic NF1 features. [26][27][28][29]45 While theoretically one would only need a sample size of n = 102 for a comparison of these six specific genotypes alongside a general group with other missense pathogenic variants (assuming a medium effect size of f 2 = 0.15, one categorical fixed effect with four categories, a significance criterion of α = 0.05, and a power of 1-β = 0.80), one would also need a reasonable number of individuals per group. As our data included only n = 2 p.844-848, n = 5 p.Met992del, n = 1 p.Met1149, n = 3 p.Arg1276, n = 4 p.Lys1423, and n = 9 p.Arg1809 individuals, we regarded our data as unsuitable for such an analysis.…”

Section: Discussionmentioning

confidence: 99%

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Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1

Ottenhoff

Rietman

Mous

et al. 2020

Genetics in Medicine

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Purpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitive deficits. The NF1 cognitive phenotype is generally considered to be highly variable, possibly due to the observed T2-weighted hyperintensities, loss of heterozygosity, NF1-specific genetic modifiers, or allelic imbalance. Methods: We investigated cognitive variability and assessed the contribution of genetic factors by performing a retrospective cohort study and a monozygotic twin case series. We included data of 497 children with genetically confirmed NF1 and an IQ assessment, including 12 monozygotic twin and 17 sibling sets. Results: Individuals carrying an NF1 chromosomal microdeletion showed significant lower full-scale IQ (FSIQ) scores than individuals carrying intragenic pathogenic NF1 variants. For the intragenic subgroup, the variability in cognitive ability and the correlation of IQ between monozygotic NF1 twin pairs or between NF1 siblings is similar to the general population. Conclusions: The variance and heritability of IQ in individuals with NF1 are similar to that of the general population, and hence mostly driven by genetic background differences. The only factor that significantly attenuates IQ in NF1 individuals is the NF1 chromosomal microdeletion genotype. Implications for clinical management are that individuals with intragenic NF1 variants that score <1.5-2 SD below the mean of the NF1 population should be screened for additional causes of cognitive disability.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1

Ottenhoff

Rietman

Mous

et al. 2020

Genetics in Medicine

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“…These missense variants are more often associated with a Noonan syndrome‐like phenotype (Koczkowska et al., 2020).…”

Section: Genetic Counseling Processmentioning

confidence: 99%

Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis—Practice Resource of the National Society of Genetic Counselors

Radtke

Bergner

Goetsch

et al. 2020

Journal of Genetic Counseling

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The goal of this practice resource is to provide genetic counselors and other healthcare professionals with a resource to reference when providing genetic counseling services to individuals and families undergoing evaluation for neurofibromatosis (NF) or who have received a diagnosis of NF, including neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). Currently, there is no known standard approach to genetic counseling in NF. This resource may be useful in a number of different healthcare settings. 1.1.1 | Pediatric or adult genetic counseling session (general genetics or specialty clinic) These sessions may occur in conjunction with a diagnosing provider, such as a physician or nurse practitioner. • Diagnostic evaluation based on clinical features and/or family history.

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“…NF1 gene has one of the highest spontaneous mutation rates and more than 3000 mutations have been recognized to date [68]. The following variants are associated with specific phenotypes: missense variants at the NF1 codons p.Arg1809, p.Met1149, p.Arg1276, and p.Lys1423 and the in-frame deletion c.2970-2972 delAAT [69][70][71]. In our series, 19 out of 35 patients underwent molecular testing for NF1 and an NF1 mutation was identified in 18 cases (Table 4).…”

Section: Discussionmentioning

confidence: 99%

Retrospective Multicentric Study on Non-Optic CNS Tumors in Children and Adolescents with Neurofibromatosis Type 1

Santoro

Picariello

Palladino

et al. 2020

Cancers

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The natural history of non-optic central nervous system (CNS) tumors in neurofibromatosis type 1 (NF1) is largely unknown. Here, we describe prevalence, clinical presentation, treatment, and outcome of 49 non-optic CNS tumors observed in 35 pediatric patients (0–18 years). Patient- and tumor-related data were recorded. Overall survival (OS) and progression-free survival (PFS) were evaluated. Eighteen patients (51%) harbored an optic pathway glioma (OPG) and eight (23%) had multiple non-optic CNS lesions. The majority of lesions (37/49) were managed with a wait-and-see strategy, with one regression and five reductions observed. Twenty-one lesions (42.9%) required surgical treatment. Five-year OS was 85.3%. Twenty-four patients progressed with a 5-year PFS of 41.4%. Patients with multiple low-grade gliomas progressed earlier and had a lower 5-year PFS than those with one lesion only (14.3% vs. 57.9%), irrespective of OPG co-presence. Non-optic CNS tumors are common in young patients with NF1. Neither age and symptoms at diagnosis nor tumor location influenced time to progression in our series. Patients with multiple lesions tended to have a lower age at onset and to progress earlier, but with a good OS.

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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

Abstract: We report 281 individuals carrying a pathogenic recurrent NF1

Cited by 106 publications

References 49 publications

Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1

Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1

Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis—Practice Resource of the National Society of Genetic Counselors

Retrospective Multicentric Study on Non-Optic CNS Tumors in Children and Adolescents with Neurofibromatosis Type 1

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