Most significantly associated rare variants in the family-based association test and their predicted pathogenicity*
| Chr:BP (hg19) | dbSNP identifier | Gene | Reference allele/ alternative allele | Variant type | PolyPhen | CADD Phred score | DANN score | Alternative allele count† | Pedigree (per-family LOD) |
|---|---|---|---|---|---|---|---|---|---|
| 10:52005095 | rs116049719 | ASAH2‡ | G/A | Nonsense | — | 35 | 0.9974 | 9 | 131 (0.31) 18 (0.42)§ 1 (0.68) 74 (−0.03) |
| 10:55566719 | rs570828018 | PCDH15 | G/A | Missense | Damaging | 19.18 | 0.9984 | 5 | 138 (0.43)¶ |
| 10:55581787 | Novel | PCDH15 | T/A | Missense | Benign | 23 | 0.9664 | 5 | 18 (0.42)§ |
| 10:64967951 | rs139722368 | JMJD1C | CTAAAC/− | Indel | — | 19.05 | — | 15 | 129 (0.24) 138 (0.43)¶ 19 (−0.124) |
| 10:64974380 | rs41274074 | JMJD1C | G/C | Missense | Benign | 15.64 | 0.8880 | 15 | 129 (0.24) 138 (0.43)¶ 19 (−0.124) |
| 10:61815652 | rs780899852 | ANK3 | G/C | Missense | Damaging | 24.3 | 0.9927 | 5 | 18 (0.42)§ |
| 10:64913602 | rs62623680 | NRBF2 | A/G | Missense | Damaging | 28.3 | 0.9980 | 6 | 17 (0.57) |
CADD = Combined Annotation Dependent Depletion; Chr:BP (hg19) = the chromosome (chr) and base pair (BP) position of each variant, based on Genome Reference Consortium Human Build 37 (GRCh37/hg19); DANN = Deleterious Annotation of genetic variants using Neural Networks; dbSNP ID = SNP identifier; LOD = logarithm of the odds (for linkage); PolyPhen = polymorphism phenotyping, functional prediction of SNP impact on protein product; SNP = single nucleotide polymorphism.
↵* Pathogenicity prediction is presented for missense variants using PolyPhen, the CADD Phred scaled score and DANN scores. A CADD Phred scaled score (42) of 20 means that the variant is among the top 1% of deleterious variants in the human genome, and a score of 30 means that the variant is in the top 0.1%. For DANN, (43) a score of 0.96 identifies 92.1% of pathogenic variations from ClinVar (www.ncbi.nlm.nih.gov/clinvar) and 18.1% of false-positive benign variations; values greater than 0.98 predict protein-disrupting or -altering variants. Positive values for the per-family LOD score indicate a positive contribution to the linkage signal from each family carrying that variant.
↵† Total number of alternative alleles observed across 117 sequenced individuals.
↵‡ Genes not expressed in the brain (defined by reads per kilobase per million [RPKM] < 1 in developmental transcriptomics RNA sequencing data, representing 65% of mapped genes) are indicated.
↵§ Variants present on the same haplotype in pedigree 18.
↵¶ Variants present on the same haplotype in pedigree 138.