Table 1.
In this table, we have summarized information on shared genomic variants in a family, in which three siblings were affected with bipolar disorder and anxiety spectrum disorders.
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(A) Potentially damaging variants in nine brain-expressed genes were shared by the affected family members. | ||||||
|---|---|---|---|---|---|---|
| Location | Gene | Transcript | Exon | Coding | Protein | Zygosity |
| 7:123109272 | IQUB | NM_178827 | 9 | c.1577T > A | p.Val526Glu | het |
| 10:64967788 | JMJD1C | NM_032776 | 10 | c.3641A > G | p.His1214Arg | het |
| 1:68152073 | GADD45A | NM_001199741 | 2 | c.85G > C | p.Glu29Gln | het |
| 3:121435874 | GOLGB1 | NM_004487 | 9 | c.983T > C | p.Val328Ala | het |
| 3:146311810 | PLSCR5 | NM_001085420 | 4 | c.350G > A | p.Arg117Gln | het |
| 3:145917659 | PLSCR4 | NM_020353 | 6 | c.565A > G | p.Met189Val | het |
| 2:58315517 | VRK2 | NM_001130480 | 6 | c.386A > G | p.Gln129Arg | het |
| 15:81274319 | MESDC2 | NM_015154 | 2 | c.418C > T | p.Leu140Phe | het |
| 1:60019796 | FGGY | NM_001113411 | 8 | c.800G > T | p.Gly267Val | het |
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(B) Quality control measures for the rare variants indicated high quality reads and good coverage. | |||||
|---|---|---|---|---|---|
| Location | Gene | Identifier | Quality score | Filter result | Average depth |
| 7:123109272 | IQUB | novel | 1148.24 | Pass | 68.1677 |
| 10:64967788 | JMJD1C | novel | 3935.47 | Pass | 141.0839 |
| 1:68152073 | GADD45A | novel | 747.91 | Pass | 27.9346 |
| 3:121435874 | GOLGB1 | rs140932474 | 4257.63 | Pass | 125.7677 |
| 3:146311810 | PLSCR5 | rs199965523 | 4061.42 | Pass | 137.5935 |
| 3:145917659 | PLSCR4 | rs139054640 | 1708.17 | Pass | 68.9742 |
| 2:58315517 | VRK2 | novel | 3801.98 | Pass | 126.9355 |
| 15:81274319 | MESDC2 | novel | 1624.88 | Pass | 68.271 |
| 1:60019796 | FGGY | rs142088608 | 2029.22 | Pass | 83.0387 |
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(C) Functional prediction algorithms indicate deleterious effects of the shared variants on protein structure and function. | |||||||
|---|---|---|---|---|---|---|---|
| Location | Gene | SIFT | SIFT prediction | PolyPhen-2 | PolyPhen-2 Prediction | MutationTaster | MutationTaster prediction |
| 7:123109272 | IQUB | 0 | Damaging | 0.998 | Probably damaging | 0.641624 | Disease-causing |
| 10:64967788 | JMJD1C | 0.04 | Damaging | 0.504 | Possibly damaging | 0.614459 | Disease-causing |
| 1:68152073 | GADD45A | 0.03 | Damaging | 0.817 | Possibly damaging | 0.384507 | Polymorphism |
| 3:121435874 | GOLGB1 | 2 | ? | −1 | ? | −1 | ? |
| 3:146311810 | PLSCR5 | 0 | Damaging | 0.999 | Probably damaging | −1 | ? |
| 3:145917659 | PLSCR4 | 0.25 | Tolerated | 0.542 | Possibly damaging | 0.283731 | Polymorphism |
| 2:58315517 | VRK2 | 0.04 | Damaging | 0.631 | Possibly damaging | 0.916062 | Disease-causing |
| 15:81274319 | MESDC2 | 0 | Damaging | 1 | Probably damaging | 0.999964 | Disease-causing |
| 1:60019796 | FGGY | 2 | ? | 0.999 | Probably damaging | 0.999565 | Disease-causing |
| Location | Gene | MutationAssessor | MutationAssessor prediction | GERP++ RS | PhyloP |
|---|---|---|---|---|---|
| 7:123109272 | IQUB | 3.16 | Predicted functional (medium) | 5.51 | 2.105 |
| 10:64967788 | JMJD1C | 1.79 | Predicted non-functional (low) | 5.58 | 2.114 |
| 1:68152073 | GADD45A | 2.265 | Predicted functional (medium) | 4.58 | 1.324 |
| 3:121435874 | GOLGB1 | 2.015 | Predicted functional (medium) | 4.54 | 2.33 |
| 3:146311810 | PLSCR5 | 3.82 | Predicted functional (high) | 5.69 | 2.679 |
| 3:145917659 | PLSCR4 | 0.58 | Predicted non-functional (neutral) | 3.69 | 0.971 |
| 2:58315517 | VRK2 | 2.32 | Predicted functional (medium) | 5.63 | 2.281 |
| 15:81274319 | MESDC2 | 2.555 | Predicted functional (medium) | 5.32 | 2.487 |
| 1:60019796 | FGGY | 3.425 | Predicted functional (medium) | 5.28 | 2.736 |
(A) describes the exact chromosomal location of the identified variant for each gene, followed by the identification number of the major gene transcript. For each variant, we identified the exon, in which the mutation was found, as well as the resulting change in the coding sequence of the gene and the amino acid change in the protein. We also indicate if the change occurred on either both alleles (homozygous) or only on one of the alleles (heterozygous).
(B) indicates if the genomic variant in the specific gene is a novel occurrence or has been described before in genomic data bases, as indicated by the rs identification number. The quality score indicates the overall quality of the sequencing reaction according to GATK. Filter results indicate if a variant met pre-specified quality control thresholds. The table also indicates the average read depth of the sequencing reaction for a particular base pair.
(C) summarizes the results of the functional prediction algorithms SIFT, PolyPhen-2, MutationTaster, and MutationAssessor. Both the scores and the interpretation are given. It also indicates the degree of evolutionary constraint at the base pair location predicted by the GERP++ RS and PhyloP scoring systems (26, 27). While not all functional predictors agree with the deleterious consequences of the base pair change, a clear trend is obvious. Functional experiments are recommended to confirm the predictions.
A ? indicates that the prediction is unknown.
The variants were found in the genes IQUB, IQ motif and ubiquitin domain containing; JMJD1C, jumonji domain containing 1C; GADD45A, growth arrest and DNA-damage-inducible, alpha; GOLGB1, golgin B1; PLSCR5, phospholipid scramblase family, member 5; PLSCR4, phospholipid scramblase family, member 4; VRK2, vaccinia related kinase 2; MESDC2, mesoderm development candidate 2; FGGY, carbohydrate kinase domain containing.