Table 2 Genes not in the consensus or discordant lists that passed FDR < 5% in the main gene burden analysis, which was based on 29,745 probands without inferred cross-continental admixture (referred to as ‘all individuals’ in the column header). P values of <7.2 × 10−7 pass Bonferroni correction. We only show the result for the most significant combination of consequence classes per gene. Additionally, we show the P value obtained by restricting the analysis to 17,029 undiagnosed probands without inferred cross-continental admixture. Both sets of P values are from a one-sided Poisson test. The Supplementary Data File shows results for all combinations of consequence classes. The Supplementary Note gives more detail on these genes, including on the putative alternative partial diagnosis in one of the ATAD2B cases that led to this individual being dropped from the analysis of undiagnosed cases
HGNC symbol | Most significant variant class | Results from all individuals | P value in undiagnosed only | Supporting evidence and notes | |
|---|---|---|---|---|---|
Observed (expected) | P value | ||||
CRELD1 | All | 6 (0.2067) | 9.08 × 10−8 | 8.83 × 10−9 | Recently implicated gene18 Cosegregation in one affected sibling Observed in an additional proband who was removed owing to admixture, plus two additional probands in a newer GeneDx datafreeze Known dominant developmental disorder gene |
KBTBD2 | LoF/functional | 2 (0.0005) | 1.25 × 10−7 | 6.77 × 10−8 | Similar phenotype in mouse model21,27 Additional case with similar phenotype identified in CENTOGENE Extremely constrained (pLI = 1) |
ZDHHC16 | LoF/LoF + LoF/functional | 3 (0.0265) | 3.04 × 10−6 | 6.05 × 10−7 | Cosegregation in one affected sibling Three additional cases with similar phenotypes identified (one from CENTOGENE, two from GeneDx) Zebrafish model shows defective telencephalon development28 |
HECTD4 | LoF/LoF | 2 (0.0042) | 8.80 × 10−6 | 2.79 × 10−6 | Recently implicated gene19 Two additional cases with similar phenotypes identified in GeneDx Extremely constrained (pLI = 1) |
ATAD2B | LoF/LoF + LoF/functional | 2 (0.0045) | 1.02 × 10−5 | 2.81 × 10−3 | Cosegregation in one affected sibling Extremely constrained (pLI = 1) Homozygous mouse knockout shows behavioral abnormalities29 One additional case with damaging biallelic missense variants identified in GeneDx Contrary evidence: limited phenotypic similarity between patients other than developmental delay or intellectual disability |
