Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia
Abstract
:1. Introduction
2. Results
2.1. Case Report
2.2. Whole-Exome Analysis
2.3. Transcriptome Analysis
2.4. Metabolome Analysis
3. Discussion
4. Materials and Methods
4.1. Consent and Approval
4.2. WES for Candidate Gene Identification
4.3. RNA-Seq for Gene Expression Analysis
4.4. Validation of Next-Generation Sequencing (NGS) Candidate Variants
4.5. Functional Validation through Metabolomics
4.5.1. Metabolite Extraction and Mass Spectrometry Analysis
4.5.2. Data Treatment
4.5.3. Metabolite Identification
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 | Family | Sex (F/M) | Ethnicity | Consanguinity | Age at Last Assessment (Years) | Age of Onset (Years) | Genetic Characteristics | |
---|---|---|---|---|---|---|---|---|
Mutation 1 | Mutation 2 | |||||||
Index | XXIV | F | Caucasian (Spanish) | No | 14 | 2.5 | c.193A>G; | c.836G>A; |
p.Met65Val | p.Arg279Gln | |||||||
1 [19] | I | M | Libyan | Yes | 8 | 0.5 | c.95A>T; | c.95A>T; |
p.Asn32Ile | p.Asn32Ile | |||||||
2 [19] | II | M | Hungarian | No | 10 | 1 | c.221A>G; | c.221A>G; |
p.Asn74Ser | p.Asn74Ser | |||||||
3 [19] | III | M | Asian (Chinese) | No | 4 | 1 | c.436T>C; | c.883_885delAAG; |
p.Cys146Arg | p.Lys295del | |||||||
4 [19] | IV | F | Caucasian (Armenian/Russian) | No | 6 | 2.5 | c.77C>T; | c.326G>A; |
p.Thr26Ile | p.Arg109His | |||||||
5 [19] | V | F | Caucasian | No | 9 | 1.5 | c.193A>G; | c.572G>A; |
p.Met65Val | p.Arg191Gln | |||||||
6 [19] | VI | F | Caucasian (Turkish) | Suspected | 18 | 4 | c.326G>A; | c.970G>A; |
p.Arg109His | p.Glu324Lys | |||||||
7 [19] | VII | M | Caucasian | No | 33 | 2 | c.395G>A; | c.461_462delAA; |
p.Gly132Asp | p.Lys154Argfs*4 | |||||||
8 [19] | VIII | F | Caucasian | No | 2 | 1 | c.281T>C; | c.785T>C; |
p.Val94Ala | p.Ile262Thr | |||||||
9 [20] | IX | F | Tunisian | Yes | 25 | 5 | c.863T>C; | c.863T>C; |
p.Phe288Ser | p.Phe288Ser | |||||||
10 [22] | X | M | Caucasian (British) | No | NA | 0 | c.69+1G>A; | c.836G>A; |
p.Asn24Asnfs55*; (prediction) | p.Arg279Gln | |||||||
11 [22] | XI | M | Caucasian | No | NA | 4 | c.916_920delTATAT; | c.938C>T; |
12 [22] | M | p.Tyr306Leufs*4 | p.Thr313Met | |||||
13 [22] | XII | M | Caucasian (Dutch) | No | NA | 2 | c.193A>G; | c.733G>A; |
p.Met65Val | p.Val245Met | |||||||
14 [22] | XIII | F | Caucasian (English) | No | NA | 3 | c.313A>T; | c.916_920delTATAT; |
p.Ile105Phe | p.Tyr306Leufs*4 | |||||||
15 [22] | XIV | F | Caucasian (English) | Yes | NA | 2 | c.836G>A; | c.836G>A; |
p.Arg279Gln | p.Arg279Gln | |||||||
16 [22] | XV | F | Norwegian | No | NA | 0.3 | c.88C>T; | c.916_920delTATAT; |
p.Pro30Ser | p.Tyr306Leufs*4 | |||||||
17 [22] | XVI | F | Caucasian (English) | No | NA | 0 | c.221A>G; | c.502G>A; |
p.Asn74Ser | p.Val168Met + splicing error | |||||||
18 [22] | XVII | F | Caucasian | No | NA | 6 | c.79A>G; | c.349G>C; |
p.Thr27Ala | p.Ala117Pro | |||||||
19 [22] | XVIII | F | Caucasian | No | NA | 0.4 | c.322C>T; | c.325C>T; |
p.His108Tyr | p.Arg109Cys | |||||||
20 [22] | XIX | F | African/American | No | NA | 2 | c.70-1G>A; | c.835C>T; |
p.Asn24Profs27* (prediction) | p.Arg279Trp | |||||||
21 [22] | XX | F | Caucasian | No | NA | 0 | c.699C>G; | c.883_885delAAG; |
p.Tyr233* | p.Lys295del | |||||||
22 [22] | XXI | M | Caucasian | No | NA | 1 | c.88C>T; | c.615delC; |
23 [22] | F | 0 | p.Pro30Ser | p.Gln206Lysfs*48 | ||||
24 [22] | XXII | F | Asian | No | NA | 3.5 | c.77C>T; | c.77C>T; |
p.Thr26Ile | p.Thr26Ile | |||||||
25 [21] | XXIII | M | Asian (Korean) | NA | NA | 5 | c.698_699insAA; | c.713A>G; |
26 [21] | F | p.Tyr233fs | p.Asp238Gly |
Patient | Symptoms at Onset 1 | Develop-mental Delay 1 | Age at Walking without Support (Months) 1 | Abnormal Cognition 1 | Cerebellar Signs | Tremor 1 | Pyramidal Signs | Dystonia | Myoclonus | Age at Wheelchair (Years) | Myopia | Dental AbN | Hypogonadotropic Hypogonadism |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Index | Delayed motor development, tremor, ataxia, dysmetria | + | 28 | + | + | + | + | + | + | 7 | + | − | − |
1 [19] | Delayed motor development | + | 22 | + | + | + | + | − | − | 3 | − | + | Too young |
2 [19] | Ataxia, tremor, head titubation | + | 18 | + | + | + | + | − | − | 9 * | − | − | Too young |
3 [19] | Delayed motor development and failure to thrive | + | Never autonomously | + | + | + | + | + | − | Always | − | − | Too young |
4 [19] | Tremor, dysmetria | + | 15 | − | + | + | + | − | − | − * | − | + | Too young |
5 [19] | Delayed motor development | + | 24 | + | + | + | + | − | − | Always * | + | − | Too young |
6 [19] | Clumsy gait, frequent falls | − | 18 | + | + | + | + | + | − | 9 (long distances) * | + | − | − |
7 [19] | Delayed motor development | + | Never autonomously | + | + | + | − | − | + | Puberty | + | − | − |
8 [19] | Delayed motor development | + | 24 (with support) | − | + | + | − | − | − | − | − | + | Too young |
9 [20] | Tremor, ataxia | − | 12 | − | + | + | + | + | + | 21 * | − | − | − |
10 [22] | NA | NA | NA | NA | + | NA | + | − | NA | NA | − | + | Too young |
11 [22] | NA | NA | NA | NA | + | NA | − | − | NA | − | − | + | − |
12 [22] | NA | NA | NA | NA | + | NA | − | − | NA | − | + | + | − |
13 [22] | NA | NA | NA | NA | + | NA | − | − | NA | − | + | − | − |
14 [22] | NA | NA | NA | NA | + | NA | − | − | NA | 12 | + | + | Too young |
15 [22] | NA | NA | NA | NA | + | NA | + | + | NA | 7 | − | − | Too young |
16 [22] | NA | NA | NA | NA | + | NA | − | + | NA | 0 | + | + | Too young |
17 [22] | NA | NA | NA | NA | + | NA | + | + | NA | 0 | + | + | Too young |
18 [22] | NA | NA | NA | NA | + | NA | + | − | NA | − | − | + | − |
19 [22] | NA | NA | NA | NA | + | NA | + | − | NA | 0 | − | + | − |
20 [22] | NA | NA | NA | NA | + | NA | + | − | NA | 11 | − | − | Too young |
21 [22] | NA | NA | NA | NA | + | NA | + | + | NA | 3 | + | + | Too young |
22 [22] | NA | NA | NA | NA | + | NA | + | + | NA | 4 | +C | + | Too young |
23 [22] | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | − | Too young |
24 [22] | NA | NA | NA | NA | + | NA | − | − | NA | − | + | + | Too young |
25 [21] | Tremor, ataxia | + | NA | + | + | + | + | NA | − | NA | + | − | − |
26 [21] | Tremor, ataxia | + | NA | + | + | + | + | NA | + | NA | + | − | − |
Patient | Diffuse Hypomyelination | Cerebellar Atrophy | Thin Corpus Callosum |
---|---|---|---|
Index | + | + | + |
1 [19] | + | − | + |
2 [19] | + | − | + |
3 [19] | + | − | + |
4 [19] | + | + | + |
5 [19] | + | + | + |
6 [19] | + | + | + |
7 [19] | + | + | + |
8 [19] | + | + | + |
9 [20] | + | + | + |
10 [22] | + | − | + |
11 [22] | + | + | + |
12 [22] | + | + | + |
13 [22] | + | + | + |
14 [22] | + | + | + |
15 [22] | + | + | + |
16 [22] | + | − | − |
17 [22] | + | + | + |
18 [22] | + | + | + |
19 [22] | + | + | + |
20 [22] | + | + | + |
21 [22] | + | − | + |
22 [22] | + | + | + |
23 [22] | NA | NA | NA |
24 [22] | + | + | + |
25 [21] | + | − | NA |
26 [21] | + | − | NA |
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Ching-López, A.; Martinez-Gonzalez, L.J.; Arrabal, L.; Sáiz, J.; Gavilán, Á.; Barbas, C.; Lorente, J.A.; Roldán, S.; Sánchez, M.J.; Gutierrez-Ríos, P. Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia. Int. J. Mol. Sci. 2021, 22, 2990. https://doi.org/10.3390/ijms22062990
Ching-López A, Martinez-Gonzalez LJ, Arrabal L, Sáiz J, Gavilán Á, Barbas C, Lorente JA, Roldán S, Sánchez MJ, Gutierrez-Ríos P. Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia. International Journal of Molecular Sciences. 2021; 22(6):2990. https://doi.org/10.3390/ijms22062990
Chicago/Turabian StyleChing-López, Ana, Luis Javier Martinez-Gonzalez, Luisa Arrabal, Jorge Sáiz, Ángela Gavilán, Coral Barbas, Jose Antonio Lorente, Susana Roldán, Maria José Sánchez, and Purificacion Gutierrez-Ríos. 2021. "Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia" International Journal of Molecular Sciences 22, no. 6: 2990. https://doi.org/10.3390/ijms22062990
APA StyleChing-López, A., Martinez-Gonzalez, L. J., Arrabal, L., Sáiz, J., Gavilán, Á., Barbas, C., Lorente, J. A., Roldán, S., Sánchez, M. J., & Gutierrez-Ríos, P. (2021). Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia. International Journal of Molecular Sciences, 22(6), 2990. https://doi.org/10.3390/ijms22062990