Abstract
Up to 84% of patients with congenital pseudarthrosis of the tibia (CPT) present with neurofibromatosis type 1 (NF1) (NF1-CPT). However, the etiology of CPT not fulfilling the NIH diagnostic criteria for NF1 (non-NF1-CPT) is not well understood. Here, we collected the periosteum tissue from the pseudarthrosis (PA) site of 43 non-NF1-CPT patients and six patients with NF1-CPT, together with the blood or oral specimen of trios (probands and unaffected parents). Whole-exome plus copy number variation sequencing, multiplex ligation-dependent probe amplification (MLPA), ultra-high amplicon sequencing, and Sanger sequencing were employed to identify pathogenic variants. The result showed that nine tissues of 43 non-NF1-CPT patients (21%) had somatic mono-allelic NF1 inactivation, and five of six NF1-CPT patients (83.3%) had bi-allelic NF1 inactivation in tissues. However, previous literature involving genetic testing did not reveal somatic mosaicism in non-NF1-CPT patients so far. In NF1-CPT patients, when the results from earlier reports and the present study were combined, 66.7% of them showed somatic NF1 inactivation in PA tissues other than germline inactivation. Furthermore, no diagnostic variants from other known genes (GNAS, AKT1, PDGFRB, and NOTCH3) related to skeletal dysplasia were identified in the nine NF1 positive non-NF1-CPT patients and six NF1-CPT patients. In conclusion, we detected evident somatic mono-allelic NF1 inactivation in the non-NF1-CPT. Thus, for pediatric patients without NF1 diagnosis, somatic mutations in NF1 are important.
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The novel variants found in this study were submitted to ClinVar (accession: SCV002014754-SCV002014759). Other datasets used during the current study are available from the corresponding authors on reasonable request.
Abbreviations
- CPT:
-
Congenital pseudarthrosis of the tibia
- NF1:
-
Neurofibromatosis type 1
- NF1-CPT:
-
CPT fulfilling the NIH diagnostic criteria for NF1
- Non-NF1-CPT:
-
CPT not fulfilling the NIH diagnostic criteria for NF1
- MNF1:
-
Mosaic NF1
- MLPA:
-
Multiplex ligation-dependent probe amplification
- PA:
-
Pseudarthrosis
- WES:
-
Whole-exome sequencing
- CNV:
-
Copy number variation
- CAL:
-
Café au lait macules
- PBS:
-
Phosphate-buffered saline
- SNV:
-
Single-nucleotide variations
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We thank all the participated patients and their families for supporting our research. We also would like to express our sincere gratitude to all those who helped us in this study.
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This work was supported by the Hunan Province Natural Science Foundation of China (Grant number: 2020JJ8005), the Health Commission of Hunan Province of China (Grant number: B2019020), Key Research and Development Program of Hunan Province (Grant number: 2020SK2113), and Clinical Research Center for Limb Deformity of Children in Hunan Province (Grant number: 2019SK4006).
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Conceptualization and investigation: ZH and HM, Funding acquisition, investigation, supervision, resources acquisition, methodology, and validation: HM, ZH, and YZ. Original draft writing and data analysis: YZ. Resources collection, idea refining, and data validation: GZ, YL, WZ, YY, ZL, and YF. Manuscript review and editing: ZH and HM. All authors read and approved the final manuscript.
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Zheng, Y., Zhu, G., Liu, Y. et al. Case series of congenital pseudarthrosis of the tibia unfulfilling neurofibromatosis type 1 diagnosis: 21% with somatic NF1 haploinsufficiency in the periosteum. Hum Genet 141, 1371–1383 (2022). https://doi.org/10.1007/s00439-021-02429-2
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DOI: https://doi.org/10.1007/s00439-021-02429-2