The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model
Abstract
:1. Introduction
2. Results
2.1. Identification of Germline Mutations
2.2. Identification of Somatic Variants
2.3. Analysis of Somatic Copy Number Changes
3. Discussion
3.1. Detection of Somatic Mosaicism
3.2. ENS-Specific Somatic Changes in DNA Copy Number
3.3. Would ENCCs with a Somatic Variant Remain to Be Sampled?
4. Materials and Methods
4.1. Patients
4.2. Sample Collection
4.3. Cell Culture and Fluorescence-Activated Cell Sorting
4.4. Amplicon-Based WES
4.5. Data Analysis and Selection of Somatic Variants
4.6. Validation of Putative Mosaic Differences
4.7. Analysis of Somatic Copy Number Changes
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Patient | ENCC Only | Blood Only | PPAE | PPAB | VAPE | Validated @ |
---|---|---|---|---|---|---|
1 | 50 | 43 | 8 | 11 | 5 | 0 |
2 | 16 | 28 | 2 | 4 | 1 | 0 |
3 | 25 | 33 | 0 | 1 | 0 | 0 |
4 # | 96 | 178 | 17 | 11 | 15 | 0 $$ |
5 | 29 | 35 | 2 | 1 | 2 | 0 |
Patient | Gene | cDNA | Type | dbSNP | Class | GnomADe | GnomADg | MisZ | pLI | FE | ME |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | FMN2 | c.162delC | FD | VUS | 0.000000 | 0.000000 | 1.42 | 0.99 | no | yes | |
1 | YWHAE | c.G142A | M | VUS | 0.000000 | 0.000000 | 3.25 | 0.96 | yes | na | |
1 | YWHAE | c.T116C | M | VUS | 0.000000 | 0.000000 | 3.25 | 0.96 | yes | na | |
1 | PHAX | c.C379T | PS | VUS | 0.000000 | 0.000000 | –0.51 | 0.00 | yes | na | |
1 | POR | c.T1231C | M | VUS | 0.000000 | 0.000000 | −0.54 | 0.00 | yes | na | |
2 | DEPDC1 | c.T1459A | M | VUS | 0.000000 | 0.000000 | −0.32 | 0.00 | yes | na | |
4 | F5 | c.A1867G | M | VUS | 0.000000 | 0.000000 | −1.30 | 0.00 | no | na | |
4 | PHRF1 | c.G1075A | M | rs551874512 | VUS | 0.000033 | 0.000032 | −1.36 | 0.95 | yes | na |
4 | MYBPC3 | c.C482A | M | VUS | 0.000000 | 0.000000 | 0.69 | 0.00 | no | na | |
4 | PACS1 | c.G1069A | M | rs750459659 | VUS | 0.000041 | 0.000032 | 4.32 | 1.00 | yes | na |
4 | OAS3 | c.C1390T | M | rs750291946 | VUS | 0.000012 | 0.000000 | −0.60 | 0.00 | yes | na |
4 | MAN2A2 | c.G478A | M | rs374688808 | VUS | 0.000012 | 0.000032 | 1.28 | 0.00 | yes | yes |
4 | SNF8 | c.G578A | M | rs775611332 | VUS | 0.000025 | 0.000000 | 0.97 | 0.29 | yes | yes |
4 | MED15 | c.C730A | M | VUS | 0.000000 | 0.000000 | 2.50 | 0.96 | yes | na | |
4 | IQCF5 | c.C283T | M | rs772101978 | VUS | 0.000100 | 0.000000 | −1.59 | 0.43 | no | na |
4 | TMEM165 | c.C782A | M | VUS | 0.000000 | 0.000000 | 1.83 | 0.94 | yes | na | |
4 | NOTCH4 | c.G1118A | M | rs745883985 | VUS | 0.000033 | 0.000032 | 2.45 | 0.00 | yes | na |
4 | DPPA5 | c.G214A | M | VUS | 0.000000 | 0.000000 | 1.64 | 0.00 | no | na | |
4 | SLC22A1 | c.C523T | M | rs768905186 | VUS | 0.000004 | 0.000000 | −0.28 | 0.00 | no | na |
4 | MGAM2 | c.G3015T | M | VUS | 0.000000 | 0.000000 | na | na | |||
4 | IKBKB | c.G809A | M | rs200841053 | VUS | 0.000024 | 0.000032 | 2.90 | 1.00 | yes | na |
5 | PCDH15 | c.G139A | M | VUS | 0.000000 | 0.000000 | −3.27 | 0.00 | no | yes | |
5 | ZNF592 | c.C3433A | M | VUS | 0.000000 | 0.000000 | 1.10 | 0.95 | yes | na |
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MacKenzie, K.C.; Garritsen, R.; Chauhan, R.K.; Sribudiani, Y.; de Graaf, B.M.; Rugenbrink, T.; Brouwer, R.; van Ijcken, W.F.J.; de Blaauw, I.; Brooks, A.S.; et al. The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model. Int. J. Mol. Sci. 2021, 22, 12354. https://doi.org/10.3390/ijms222212354
MacKenzie KC, Garritsen R, Chauhan RK, Sribudiani Y, de Graaf BM, Rugenbrink T, Brouwer R, van Ijcken WFJ, de Blaauw I, Brooks AS, et al. The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model. International Journal of Molecular Sciences. 2021; 22(22):12354. https://doi.org/10.3390/ijms222212354
Chicago/Turabian StyleMacKenzie, Katherine C., Rhiana Garritsen, Rajendra K. Chauhan, Yunia Sribudiani, Bianca M. de Graaf, Tim Rugenbrink, Rutger Brouwer, Wilfred F. J. van Ijcken, Ivo de Blaauw, Alice S. Brooks, and et al. 2021. "The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model" International Journal of Molecular Sciences 22, no. 22: 12354. https://doi.org/10.3390/ijms222212354