Table 1 Candidate genes identified by trio pooled-WES in this study.
Gene | Zigosity | Inheritance | Variant Type | gnomAD MAF | Domino Score | In silico predictors | Gene intolerance scores | Rationale for inclusion as a candidate gene | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
REVEL | CADD | AlphaMissense | SIFT | SpliceAI | PhyloP | pLi | Missense Z score | |||||||
APOO | Heterozygous | De novo | Stopgain | 0.000000912 | – | – | 38 | – | – | – | 3.95 | – | – | De novo LoF variant, observed in a single individual in gnomAD, within an X-linked gene previously suggested as a candidate for NDD [42]. |
CCR7 | Heterozygous | De novo | Missense | – | 0.7 | 0.73 | 26.8 | 0.986 | 0 | – | 7.84 | – | 2.69 | De novo missense variant in a likely dominant gene; unanimously predicted deleterious, absent from gnomAD, and affecting a highly conserved residue |
CDC42BPA | Heterozygous | De novo | Frameshift | – | 0.6 | – | – | – | – | – | 9.325 | 1 | – | De novo LoF variant in a likely dominant, haploinsufficient gene, absent from gnomAD. |
MAPK7 | Heterozygous | De novo | Missense | 0.00000137 | 0.9 | 0.82 | 27 | 0.993 | 0 | – | 5.796 | – | 2.09 | De novo missense variant in a likely dominant gene; unanimously predicted deleterious, observed in a single individual in gnomAD, and affecting a highly conserved residue |
MED1 | Heterozygous | De novo | Frameshift | – | 0.9 | – | – | – | – | – | 9.633 | 1 | – | De novo LoF variant in a likely dominant, haploinsufficient gene, absent from gnomAD. |
PITPNM2 | Heterozygous | De novo | Missense | – | 0.7 | 0.6 | 25.3 | 0.777 | 0 | – | 7.803 | – | 4.33 | De novo missense variant in a likely dominant gene, intolerant to missense variation. The variant is unanimously predicted to be deleterious by in silico tools, absent from gnomAD, and affects a highly conserved residue. |
PTPRT | Heterozygous | De novo | Missense | – | 0.9 | 0.85 | 24.9 | 0.989 | 0.01 | – | 9.809 | – | 3.22 | De novo missense variant in a likely dominant gene, intolerant to missense variation. The variant is unanimously predicted to be deleterious by in silico tools, absent from gnomAD, and affects a highly conserved residue. |
RYR3 | Heterozygous | De novo | Splicing | – | 0.9 | – | 34 | – | – | 0.96 | 9.993 | 1 | – | De novo splice-site variant, absent from gnomAD and predicted to alter splicing at a highly conserved residue. The variant is located in a likely dominant, haploinsufficient gene previously proposed as a candidate for NDD [43] |
TRADD | Heterozygous | De novo | Stopgain | – | 0.8 | – | 35 | – | 0.773 | 0.01 | – | De novo LoF variant in a likely dominant gene. The variant is absent from gnomAD. | ||
ZBTB17 | Heterozygous | De novo | Frameshift | – | 0.9 | – | – | – | – | – | 5.478 | 1 | – | De novo LoF variant in a likely dominant, haploinsufficient gene, absent from gnomAD. |
ZNF608 | Heterozygous | De novo | Stopgain | – | 0.9 | – | 39 | – | – | – | 2.409 | 1 | – | De novo LoF variant in a likely dominant, haploinsufficient gene, absent from gnomAD. |
ZNF75D | Hemizygous | Maternal | Splicing | – | – | – | 23.2 | – | – | 0.6 | 0.687 | – | – | Hemizygous splicing variant in an X-linked gene, inherited from the mother. In silico predictors indicate an alteration of splicing, and the variant is absent from gnomAD. |
ANGPTL2 | Homozygous | Biallelic | Stopgain | 0.00000205 | – | – | 44 | – | – | – | 2.776 | 0.01 | – | Homozygous LoF variant in a likely recessive gene; low pLI (haploinsufficiency metric, not indicative of recessive genes). No LoF variants reported in homozygosity in gnomAD. |
