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Open AccessArticle

Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children

1
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center—Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
2
Department of Pediatrics, Shanghai Children’s Medical Center—Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
3
Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, USA
4
Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
Genes 2019, 10(11), 847; https://doi.org/10.3390/genes10110847
Received: 5 July 2019 / Revised: 8 October 2019 / Accepted: 23 October 2019 / Published: 26 October 2019
(This article belongs to the Special Issue Neurofibromatosis 1 Genetics)
Background: Neurofibromatosis 1 (NF1) is one of the most common dominantly inherited genetic disorders worldwide, with an age-dependent phenotypic expression. Exploring the mutational spectrum and clinical presentation of NF1 patients at different ages from a diverse population will aid the understanding of genotype–phenotype correlations. Methods: In this study, 95 Chinese children with clinical suspicion of NF1 mainly due to the presence of multiple café-au-lait macules (CALMs) were subjected to medical exome-sequencing analysis and Sanger confirmation of pathogenic variants. Clinical presentations were evaluated regarding dermatological, ocular, neurological, and behavioral features. Results: Pathogenic or likely pathogenic NF1 variants were detected in 71.6% (68/95) of patients; 20 pathogenic variants were not previously reported, indicating that Chinese NF1 patients are still understudied. Parental Sanger sequencing confirmation revealed 77.9% of de novo variants, a percentage that was much higher than expected. The presence of a higher number of NF1-related features at young ages was correlated with positive diagnostic findings. In addition to CALMs, neurological and behavioral features had a high expression among Chinese NF1 children. We attempted to correlate short stature with the locations of the pathogenic variants across the NF1 gene. It is interesting to notice that variants detected in the C-terminal region of the NF1 gene were less likely to be associated with short stature among the NF1 patients, whereas variants at the N-terminal were highly penetrant for the short stature phenotype. Conclusion: Novel NF1 pathogenic variants are yet to be uncovered in under-studied NF1 patient populations; their identification will help to reveal novel genotype–phenotype correlations. View Full-Text
Keywords: neurofibromatosis 1; café-au-lait macules; novel variants; exome; short stature neurofibromatosis 1; café-au-lait macules; novel variants; exome; short stature
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Yao, R.; Yu, T.; Xu, Y.; Yu, L.; Wang, J.; Wang, X.; Wang, J.; Shen, Y. Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children. Genes 2019, 10, 847.

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