Novel Variants and Clinical Characteristics of 16 Patients from Southeast Asia with Genetic Variants in Neurofibromin-1

Grace Lin; Heming Wei; Angeline H. M. Lai; Ee-Shien Tan; Jiin Ying Lim; Breana Cham; Simon Ling; Saumya S. Jamuar; Ene-Choo Tan

doi:10.1055/s-0041-1736457

Journal of Pediatric Genetics, Table of Contents

J Pediatr Genet 2023; 12(02): 135-140
DOI: 10.1055/s-0041-1736457

Original Article

Novel Variants and Clinical Characteristics of 16 Patients from Southeast Asia with Genetic Variants in Neurofibromin-1

Grace Lin‡^*

¹Research Laboratory, KK Women's and Children's Hospital, Singapore

,

Heming Wei‡^*

¹Research Laboratory, KK Women's and Children's Hospital, Singapore

,

Angeline H. M. Lai

²Department of Pediatrics, Genetics Service, KK Women's and Children's Hospital, Singapore

³SingHealth Duke-NUS Paediatrics Academic Programme, Singapore

,

Ee-Shien Tan

²Department of Pediatrics, Genetics Service, KK Women's and Children's Hospital, Singapore

³SingHealth Duke-NUS Paediatrics Academic Programme, Singapore

,

Jiin Ying Lim

²Department of Pediatrics, Genetics Service, KK Women's and Children's Hospital, Singapore

,

Breana Cham

²Department of Pediatrics, Genetics Service, KK Women's and Children's Hospital, Singapore

,

Simon Ling

³SingHealth Duke-NUS Paediatrics Academic Programme, Singapore

⁴Department of Pediatrics, Neurology Service, KK Women's and Children's Hospital, Singapore

,

Saumya S. Jamuar

²Department of Pediatrics, Genetics Service, KK Women's and Children's Hospital, Singapore

³SingHealth Duke-NUS Paediatrics Academic Programme, Singapore

,

Ene-Choo Tan

¹Research Laboratory, KK Women's and Children's Hospital, Singapore

³SingHealth Duke-NUS Paediatrics Academic Programme, Singapore

› Author Affiliations

Abstract

Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders. It is caused by mutations in the neurofibromin-1 gene (NF1) and affects the formation and growth of nerve tissues. More than 3,600 pathogenic variants in the NF1 gene have been identified from patients with most of the germline variants are from the Western populations. We found 16 patients (15 Chinese and 1 Asian Indian) who had heterozygous variants in NF1 through targeted next-generation sequencing. There were 15 different variants: 4 frameshift, 4 nonsense, 5 missense, and 2 splice variants. One nonsense variant and three frameshift variants had never been reported in any population or patient database. Twelve of the 16 patients met the NF1 diagnostic criteria, and each was found to have a pathogenic or likely pathogenic variant. Three different missense variants of unknown significance were discovered in the other four patients who did not meet NF1 diagnostic criteria. Our findings add four novel variants to the list of genetic mutations linked to NF1's various clinical manifestations.

Keywords

neurofibromatosis type 1 - NF1 variants - café-au-lait spots - Lisch nodules - optic pathway glioma

Full Text

References

References
1 Kresak JL, Walsh M. Neurofibromatosis: a review of NF1, NF2, and schwannomatosis. J Pediatr Genet 2016; 5 (02) 98-104
2 Anderson JL, Gutmann DH. Neurofibromatosis type 1. Handb Clin Neurol 2015; 132: 75-86
3 Evans DG, Howard E, Giblin C. et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A 2010; 152A (02) 327-332
4 Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol 2005; 141 (01) 71-74
5 Kallionpää RA, Uusitalo E, Leppävirta J, Pöyhönen M, Peltonen S, Peltonen J. Prevalence of neurofibromatosis type 1 in the Finnish population. Genet Med 2018; 20 (09) 1082-1086
6 Uusitalo E, Leppävirta J, Koffert A. et al. Incidence and mortality of neurofibromatosis: a total population study in Finland. J Invest Dermatol 2015; 135 (03) 904-906
7 Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Primers 2017; 3: 17004
8 Bergqvist C, Servy A, Valeyrie-Allanore L, Ferkal S, Combemale P, Wolkenstein P. NF France Network. Neurofibromatosis 1 French national guidelines based on an extensive literature review since 1966. Orphanet J Rare Dis 2020; 15 (01) 37
9 Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL. Neurofibromatosis type 1 revisited. Pediatrics 2009; 123 (01) 124-133
10 DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 2000; 105 (3 Pt 1): 608-614
11 Friedman JM. Neurofibromatosis 1. In: Adam MP, Ardinger HH, Pagon RA. et al, eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2019
12 Upadhyaya M, Huson SM, Davies M. et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet 2007; 80 (01) 140-151
13 Ledbetter DH, Rich DC, O'Connell P, Leppert M, Carey JC. Precise localization of NF1 to 17q11.2 by balanced translocation. Am J Hum Genet 1989; 44 (01) 20-24
14 Wallace MR, Marchuk DA, Andersen LB. et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990; 249 (4965): 181-186
15 Abramowicz A, Gos M. Neurofibromin in neurofibromatosis type 1 - mutations in NF1 gene as a cause of disease. Dev Period Med 2014; 18 (03) 297-306
16 Cawthon RM, Weiss R, Xu GF. et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 1990; 62 (01) 193-201
17 White R, O'Connell P. Identification and characterization of the gene for neurofibromatosis type 1. Curr Opin Genet Dev 1991; 1 (01) 15-19
18 Li Y, O'Connell P, Breidenbach HH. et al. Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics 1995; 25 (01) 9-18
19 Ballester R, Marchuk D, Boguski M. et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 1990; 63 (04) 851-859
20 Scheffzek K, Ahmadian MR, Wiesmüller L. et al. Structural analysis of the GAP-related domain from neurofibromin and its implications. EMBO J 1998; 17 (15) 4313-4327
21 Shapira S, Barkan B, Friedman E, Kloog Y, Stein R. The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways. Cell Death Differ 2007; 14 (05) 895-906
22 Brems H, Legius E. Legius syndrome, an update. Molecular pathology of mutations in SPRED1. Keio J Med 2013; 62 (04) 107-112
23 Jouhilahti EM, Peltonen S, Heape AM, Peltonen J. The pathoetiology of neurofibromatosis 1. Am J Pathol 2011; 178 (05) 1932-1939
24 Chang X, Wang K. wANNOVAR: annotating genetic variants for personal genomes via the web. J Med Genet 2012; 49 (07) 433-436
25 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
26 Stumpf D, Alksne J, Annegers J. et al; National Institutes of Health Consensus Development Conference. Neurofibromatosis. Conference statement. Arch Neurol 1988; 45 (05) 575-578
27 Lubs ML, Bauer MS, Formas ME, Djokic B. Lisch nodules in neurofibromatosis type 1. N Engl J Med 1991; 324 (18) 1264-1266
28 Nichols JC, Amato JE, Chung SM. Characteristics of Lisch nodules in patients with neurofibromatosis type 1. J Pediatr Ophthalmol Strabismus 2003; 40 (05) 293-296
29 De Luca A, Schirinzi A, Buccino A. et al. Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum Mutat 2004; 23 (06) 629
30 Zhang J, Tong H, Fu X. et al. Molecular characterization of NF1 and neurofibromatosis type 1 genotype-phenotype correlations in a Chinese population. Sci Rep 2015; 5: 11291
31 Bonatti F, Adorni A, Matichecchia A. et al. Patterns of novel alleles and genotype/phenotype correlations resulting from the analysis of 108 previously undetected mutations in patients affected by neurofibromatosis type I. Int J Mol Sci 2017; 18 (10) E2071
32 Yao R, Yu T, Xu Y. et al. Clinical presentation and novel pathogenic variants among 68 Chinese neurofibromatosis 1 children. Genes (Basel) 2019; 10 (11) E847
33 Xu W, Yang X, Hu X, Li S. Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing. Int J Mol Med 2014; 34 (01) 53-60
34 Wu-Chou YH, Hung TC, Lin YT. et al. Genetic diagnosis of neurofibromatosis type 1: targeted next-generation sequencing with Multiple Ligation-Dependent Probe Amplification analysis. J Biomed Sci 2018; 25 (01) 72
35 Ratner N, Miller SJ. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer 2015; 15 (05) 290-301