Table 1:
Candidate genes from the trio-WES data
| Gene | Description | OMIM disease | Nucleotide Change (hg19, cDNA) |
Protein Change (AA, transcript) |
Inheritance | In silico prediction scores | gnomAD frequency |
Exclusion |
|---|---|---|---|---|---|---|---|---|
| AMER2 | APC membrane recruitment protein 2 | NONE | chr13: 25743858 T>C c.1900A>G chr13: 25745168 A>G c.590T>C | p.Met634Val NP_689917 p.Leu197Pro NP_689917 | Compound heterozygous | CADD (0.001) SIFT (Tolerated; 1.000) PolyPhen2(BENIGN; 0.000) CADD (24.4) SIFT (DAMAGING; 0.003) PolyPhen2(P. DAMAGING; 0.986) | 0 0 |
Limited knowledge of gene function + one variant is predicted benign |
| DNAH3 | dynein axonemal heavy chain 3 | NONE | chr16: 20975457 T>C c.9749A>G chr16: 20959830 T>C c.11318A>G | p.Lys3250Arg NP_060009 p.Tyr3773Cys NP_060009 | Compound heterozygous | CADD (15.46) SIFT (DAMAGING; 0.001) PolyPhen2(BENIGN; 0.109) CADD (17.34) SIFT (DAMAGING; 0.044) PolyPhen2(BENIGN; 0.053) | 0.001627 4 Hom 0.004640 44 Hom | Does not fit limited knowledge of gene function + one variant observed in 44 homozygotes in gnomAD |
| GAS2L2 | growth arrest specific 2 like 2 | NONE | chr17: 34074164 G>T c.956C>A chr17: 34079730 C>T c.140G>A | p.Pro319His NP_644814 p.Gly47Glu NP_644814 | Compound heterozygous | CADD (24.2) SIFT (DAMAGING; 0.001) PolyPhen2(P. DAMAGING; 1.000) CADD (24.5) SIFT (Tolerated; 0.192) PolyPhen2(P. DAMAGING; 0.884) | 4.063e-6 0 Hom 0.0006211 0 Hom | Does not fit gene function |
| MGAM2 | maltase-glucoamylase 2 (putative) | NONE | chr7: 141840614 T>A c.1099T>A chr7: 141831870 G>A c.560G>A | p.Ser367Thr NP_001280555 p.Ser187Asn NP_001280555 | Compound heterozygous | CADD (23.1) SIFT (Tolerated; 0.642) PolyPhen2(BENIGN; 0.026) CADD (23.8) SIFT (DAMAGING; 0.050) PolyPhen2(BENIGN; 0.010) | 0.0001769 0 Hom 0.003703 16 Hom | Does not fit gene function + one variant was observed in 16 homozygotes in gnomAD |
| SRGAP1 | SLIT-ROBO Rho GTPase activating protein 1 | {Thyroid cancer, nonmedullary, 2}, AD, 188470 | chr12: 64458925 G>A c.1051G>A chr12: 64502714 A>C c.1816A>C chr12: 64521811 A>G c.2711A>G | p.Val351Ile NP_065813 p.Ile606Leu NP_065813 p.Asn904Ser NP_065813 | Compound heterozygous | CADD (23.6) SIFT (Tolerated; 0.051) PolyPhen2(BENIGN; 0.007) CADD (10.05) SIFT (Tolerated; 1.000) PolyPhen2(BENIGN; 0.045) CADD (0.006) SIFT (Tolerated; 0.770) PolyPhen2(BENIGN; 0.000) | 8.160e-6 0 Hom 0.0001111 0 Hom 0.0002742 1 Hom | Does not fit phenotype or mode of inheritance + two variants are predicted benign |
| TEX15 | testis expressed 15, meiosis, and synapsis associated | NONE | chr8: 30703949 C>T c.2585G>A chr8: 30705135 A>C c.1399T>G | p.Arg862His NP_112561 p.Trp467Gly NP_112561 | Compound heterozygous | CADD (5.474) SIFT (Tolerated; 1.000) PolyPhen2(BENIGN; 0.000) CADD (0.857) SIFT (Tolerated; 0.329) PolyPhen2(BENIGN; 0.000) | 2.897e-5 0 Hom 2.858e-5 0 Hom | Does not fit gene function + both variants are predicted benign |
| VWDE | von Willebrand factor D and EGF domains | NONE | chr7: 12370825 T>C chr7: 12412800 G>A c.1390C>T | NA p.Arg464Cys NP_001129396 | Compound heterozygous | CADD (21.7) SPLICE_ACCEPTOR VARIANT CADD (34) SIFT (DAMAGING; 0.000) PolyPhen2(P. DAMAGING; 1.000) | 3.366e-5 0 Hom 0.0001387 0 Hom | Does not fit the limited knowledge of gene function |
| KCNJ6 | potassium voltage-gated channel subfamily J member 6 | Keppen-Lubinsky syndrome, AD, 614098 | chr21: 39086948 A>C c.512T>G | p.Leu171Arg NP_002231 | Heterozygous De novo | CADD (25.8) SIFT (DAMAGING; 0.001) PolyPhen2(P. DAMAGING; 1.000) | 0 | Fits with reported phenotype and predicted to be damaging |