Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing
Abstract
:1. Introduction
2. Results
2.1. Case Report
2.1.1. Case 1
2.1.2. Case 2
2.2. Identification of Pathogenic Variants
2.2.1. Case 1
2.2.2. Case 2
2.3. Estimation of Minimal Sequencing Depth for Genetic Diagnosis
3. Discussion
4. Materials and Methods
4.1. Patients and Human Ethics
4.2. Gene-Panel and Next-Generation Sequencing
4.3. Variant Discovery and Annotation
4.4. Pathogenic Variant Validation and Cascade Screening
4.5. Down-Sampling Experiment
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
CMT | Charcot-Marie-Tooth Disease |
DI-CMT | Dominant intermediate CMT |
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Gene | CMT Phenotype | Inheritance | Chromosome Location |
---|---|---|---|
KIF1B | CMT 2A1 | AD | 1p36.22 |
MFN2 | CMT 2A2A & 2A2B | AD, AR | 1p36.22 |
YARS | Dominant intermediate CMT (DI-CMT) type C | AD | 1p35.1 |
LMNA | CMT 2B1 | AR | 1q22 |
MPZ | DI-CMT type D, CMT 1B, 2I & 2J | AD | 1q23.3 |
RAB7A | CMT 2B | AD | 3q21.3 |
SH3TC2 | CMT 4C | AR | 5q32 |
FIG4 | CMT 4J | AR | 6q21 |
GARS | CMT 2D | AD | 7p14.3 |
HSPB1 | CMT 2F | AD | 7q11.23 |
NEFL | CMT 1F & 2E | AD, AR | 8p21.2 |
GDAP1 | Recessive intermediate CMT type A, CMT 2K & 4A | AD, AR | 8p21.11 |
NDRG1 | CMT 4D | AR | 8q24.22 |
EGR2 | CMT 1D | AD | 10q21.3 |
SBF2 | CMT 4B2 | AR | 11p15.4 |
MTMR2 | CMT 4B1 | AR | 11q21 |
FGD4 | CMT 4H | AR | 12p11.21 |
TRPV4 | Hereditary motor and sensory neuropathy (HMSN) IIc | AD | 12q24.11 |
HSPB8 | CMT 2L | AD | 12q24.23 |
LITAF | CMT 1C | AD | 16p13.13 |
AARS | CMT 2N | AD | 16q22.1 |
PMP22 | CMT 1A & 1E | AD | 17p12 |
DNM2 | DI-CMT type B, CMT 2M | AD | 19p13.2 |
PRX | CMT 4F | AR | 19q13.2 |
MED25 | CMT 2B2 | AR | 19q13.33 |
GJB1 | X-linked dominant CMT type 1 | XLD | Xq13.1 |
PRPS1 | X-lined recessive CMT type 5 | XLR | Xq22.3 |
Case | Variant | Gene (Variant Type) | wANNOVAR (Exome Aggregation Consortium (ExAC) Overall Minor Allele Frequency (MAF)) | MutationTaster Prediction (Prediction Probability, Pcorrect) | KGGSeq Prediction (Disease-Casual Probability, Pdisease) |
---|---|---|---|---|---|
1 | chr1:156109095_156109095delA LMNA:NM_170707:cDNA.2405_2405delA | Lamin A/C (Heterozygous 3′ UTR indel in a poly-A stretch) * | (excluded) 1 | Disease-causing (Pcorrect > 0.999) | No prediction 2 |
chr7:75932279G>A HSPB1:NM_001540:c.G250A (p.G84R) | Heat shock protein family B member 1 (Homozygous nonsynonymous SNP) | Shortlisted (no ExAC data) | Disease-causing (Pcorrect > 0.999) | Disease-causing (Pdisease = 0.681) | |
chr11:9861208G>C SBF2:NM_030962:c.C3292G (p.L1098V) | SET binding factor 2 (Heterozygous nonsynonymous SNP) | Shortlisted (MAF = 0.0209) | Polymorphism (Pcorrect = 0.054) 3 | Non-disease-causing (Pdisease = 3.46 × 10−4) | |
chr11:95595177A>G MTMR2:NM_016156: c.T447C (p.Y149Y) | Myotubularin related protein 2 (Heterozygous synonymous SNP) | Shortlisted (MAF = 2.527 × 10−5, all from South Asian data in ExAC) | Disease-causing (Pcorrect = 1) | No prediction 2 | |
2 | chr1:10342522G>A KIF1B:NM_015074:c.G1227A (p.T409T) | Kinesin family member 1B (Heterozygous synonymous SNP) | Shortlisted (MAF = 0.0328) | Polymorphism (Pcorrect = 2.98 × 10−17) 3 | (filtered) 4 |
chr1:10397567A>G KIF1B:NM_015074:c.A3260G (p.Y1087C) | Kinesin family member 1B (Heterozygous synonymous SNP) | Shortlisted (MAF = 0.0325) | Polymorphism (Pcorrect = 5.41 × 10−11) 3 | Non-disease-causing (Pdisease = 0.039) | |
chr1:156109095_156109095delA LMNA: NM_170707:cDNA.2405_2405delA | Lamin A/C (Heterozygous 3′ UTR indel in a poly-A stretch) * | (excluded) 1 | Disease-causing (Pcorrect > 0.999) | No prediction 2 | |
chr8:75272419C>T GDAP1:NM_018972:c.C358T (p.R120W) | Ganglioside-induced differentiation-associated protein 1 (Heterozygous nonsynonymous SNP) | Shortlisted (no ExAC data) | Disease-causing (Pcorrect > 0.999) | Disease-causing (Pdisease = 0.500) | |
chr11:9990017G>A SBF2:NM_030962:c.C1471T (p.L491F) | SET binding factor 2 (Heterozygous nonsynonymous SNP) | Shortlisted (no ExAC data) | Disease-causing (Pcorrect > 0.999) | Non-disease-causing (Pdisease = 0.044) |
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Ho, C.-C.; Tai, S.-M.; Lee, E.C.-N.; Mak, T.S.-H.; Liu, T.K.-T.; Tang, V.W.-L.; Poon, W.-T. Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing. Int. J. Mol. Sci. 2017, 18, 770. https://doi.org/10.3390/ijms18040770
Ho C-C, Tai S-M, Lee EC-N, Mak TS-H, Liu TK-T, Tang VW-L, Poon W-T. Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing. International Journal of Molecular Sciences. 2017; 18(4):770. https://doi.org/10.3390/ijms18040770
Chicago/Turabian StyleHo, Chi-Chun, Shuk-Mui Tai, Edmond Chi-Nam Lee, Timothy Shin-Heng Mak, Timothy Kam-Tim Liu, Victor Wai-Lun Tang, and Wing-Tat Poon. 2017. "Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing" International Journal of Molecular Sciences 18, no. 4: 770. https://doi.org/10.3390/ijms18040770