Table 3.
Rare variants detected and validated in this study.
| Family-ID | Gene | c.DNA | Protein | SNPdb | Frequency | Prediction tools | Screened individuals-genotypes | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SHGPdb | 1000G | ExAC | Kaviar | CADD(phred) | PredictSNP2 (%) | FATHMM-MKL (score) | ExAC (pLI/Z score) | |||||||||||||
| F1 | – | UM | UF | P (M) | AS (M) | AS (M) | AS (M) | US (F) | US (M) | |||||||||||
| ACIN1 | NM_001164816.2:c.214G>T | NP_001158288.1:p.(Asp72Tyr) | – | 0.000420345 | 0 | – | – | 23.5 | Neutral (63) | 0.85074 | 1.00/2.98 | HET | HOM | HET | HOM | HOM | HOM | HOM | HOM | |
| LRRK1a | NC_000015.9 (NM_024652.6):c.2687-2A>G | – | – | 0 | 0 | – | – | 33 | Deleterious (63) | 0.98391 | 0.0/3.12 | HET | HET | HOM | HOM | HET | HOM | HET | HET | |
| F2 | No candidate variants found | |||||||||||||||||||
| F5 | UM | UF | P (M) | US (F) | US (M) | |||||||||||||||
| DIAPH3a | NM_001258366.2:c.2881G>A | NP_001245295.1:p.(Glu961Lys) | – | 0.004203447 | 0 | 3.39E−05 | 2.59E−05 | 21.3 | Neutral (63) | 0.90278 | 0.0/−0.42 | WT | HET | HET | HET | HET | ||||
| LIMCH1 | NM_001112720.3:c.1174G>A | NP_001106191.1:p.(Gly392Arg) | – | 0.005884826 | 0 | 0.0001 | 7.76E−05 | 25.3 | Deleterious (87) | 0.99105 | 1.00/−0.11 | HET | HET | HET | HET | HET | ||||
| LIMCH1 | NM_001112720.3:c.1942C>T | NP_001106191.1:p.(Arg648Cys) | – | 0.001261034 | 0 | 1.30E−05 | 6.50E−06 | 34 | Deleterious (82) | 0.85122 | 1.00/−0.11 | HET | WT | HET | HET | WT | ||||
| NEK4 | NM_001193533.2:c.671C>T | NP_001180462.1:p.(Ser224Phe) | – | 0.002101723 | 0 | – | – | 21.1 | Deleterious (87) | 0.93070 | 0.0/−0.19 | HET | WT | HET | WT | WT | ||||
| F7 | UM | UF | P (M) | AS (M) | ||||||||||||||||
| PCLOa | NM_014510.3:c.10918T>C | NP_055325.2:p.(Phe3640Leu) | – | 0.000420345 | 0 | – | – | 28.2 | Deleterious (82) | 0.98562 | 1.00/−4.32 | HET | HET | HOM | WT | |||||
| ACCS | NM_001127219.2:c.1370G>A | NP_001120691.1:p.(Arg457His) | – | 0.002101723 | 0 | 1.65E−05 | 1.29E−05 | 26.8 | Deleterious (87) | 0.97866 | 0.0/−0.64 | WT | HET | HET | WT | |||||
| F10 | UM | UF | P (F) | AS (M) | ||||||||||||||||
| CRELD2a | NM_001135101.3:c.295G>A | NP_001128573.1:p.(Glu99Lys) | – | 0.000420345 | 0 | 2.01E−05 | 1.29E−05 | 27.5 | Deleterious (87) | 0.97981 | 0.0/−0.01 | WT | HET | HET | WT | |||||
| F12 | UM | UF | P (F) | |||||||||||||||||
| THBS4 | NM_003248.6:c.2738A>G | NP_003239.2:p.(Asp913Gly) | – | 0.000420345 | 0 | – | – | 32 | Deleterious (87) | 0.95833 | 0.0/0.85 | HET | WT | HET | ||||||
| PDHA1 | NM_001173456.1:c.812G>A | NP_001166927.1:p.(Arg271His) | – | 0 | 0 | – | – | 33 | Deleterious (87) | 0.97536 | 0.99/2.78 | WT | WT | HET | ||||||
| F14 | UM | UF | P (M) | US (F) | US (M) | |||||||||||||||
| PTP4A3a | NM_032611.3:c.241G>A | NP_116000.1:p.(Val81Met) | – | 0 | 0 | – | – | 25.6 | Deleterious (87) | 0.96047 | 0.13/1.62 | HET | HET | HOM | HET | HOM | ||||
| TMEM183A | NM_138391.6:c.231G>C | NP_612400.3:p.(Gln77His) | – | 0.007566204 | 0 | – | – | 21.6 | Deleterious (87) | 0.93121 | 0.95/2.54 | HET | HET | HOM | WT | HOM | ||||
| F15 | UM | UF | P (F) | US (M) | US (F) | US (F) | ||||||||||||||
| PPFIBP1 | NC_000012.11(NM_177444.3):c.1633 + 5G>A | – | – | 0.001261034 | 0 | 0 | 0 | 14.39 | Deleterious (91) | 0.90405 | 0.0/−0.17 | WT | HET | HET | HET | WT | WT | |||
| PTCH1a | NM_000264.5:c.3940C>T | NP_000255.2:p.(Pro1314Ser) | – | 0.000186116 | 0.000798722 | 0.0005 | 0.0003946 | 22.6 | Deleterious (87) | 0.99389 | 1.00/2.86 | HET | WT | HET | HET | HET | HET | |||
| ZFHX3a,b | NM_006885.4:c.6685C>G | NP_008816.3:p.(Pro2229Ala) | – | 0.009667928 | 0 | 3.30E−05 | 2.59E−05 | 22.9 | Neutral (65) | 0.99653 | 1.00/−1.68 | WT | HET | HET | HET | HET | HET | |||
| F16 | UM | UF | P (M) | US (M) | ||||||||||||||||
| KMT2Aa | NM_001197104.2:c.9962C>T | NP_001184033.1:p.(Thr3321Ile) | – | 0.006073598 | 0.000199681 | 0.0002 | 0.0001876 | 21.9 | Neutral (89) | 0.85724 | 1.00/6.64 | WT | HET | HET | WT | |||||
| NLE1 | NM_018096.5:c.313C>T | NP_060566.2:p.(Arg105Cys) | – | 0 | 0 | 2.47E−05 | 6.50E−06 | 28.2 | Deleterious (87) | 0.95952 | 0.05/1.07 | WT | HET | HET | WT | |||||
| F17 | UM | UF | P (F) | AS (M) | US (M) | US (M) | ||||||||||||||
| ACSS3 | NM_024560.4:c.802G>A | NP_078836.1:p.(Gly268Ser) | – | 0.000420345 | 0 | – | – | 22.2 | Deleterious (87) | 0.96726 | 0.0/0.30 | HET | WT | HET | WT | HET | HET | |||
| SYNE1a | NM_182961.4:c.5843G>T | NP_892006.3:p.(Cys1948Phe) | – | 0 | 0 | 5.77E−05 | 5.17E−05 | 25.6 | Deleterious (82) | 0.99237 | 0.0/−0.95 | WT | HET | HET | WT | HET | HET | |||
| NBASa | NM_015909.4:c.4692G>T | NP_056993.2:p.(Gln1564His) | – | 0 | 0 | 2.49E−05 | 6.50E−06 | 23.1 | Neutral (63) | 0.83271 | 0.0/−3.06 | WT | HET | HET | WT | HET | HET | |||
| F19 | UM | AF | P (M) | US (F) | US (F) | |||||||||||||||
| DNAH1 | NM_015512.5:c.8854A>C | NP_056327.4:p.(Ile2952Leu) | – | 0 | 0 | – | – | 22.1 | Neutral (63) | 0.93847 | 0.0/−0.89 | WT | HET | HET | HET | WT | ||||
| PLCB2a | NM_001284297.2:c.1273C>T | NP_001271226.1:p.(Arg425Trp) | rs369261333 | 0 | 0 | 3.32E−05 | 3.23E−05 | 17.48 | Deleterious (82) | 0.88593 | 0.0/1.53 | HET | WT | HET | WT | WT | ||||
| SRRM2 | NM_016333.4:c.6970C>G | NP_057417.3:p.(Pro2324Ala) | – | 0 | 0 | 0.0001 | 0.0001035 | 22.7 | Neutral (89) | 0.89484 | NA | HET | HET | HET | HET | HET | ||||
| TLK2 | NM_006852.5:c.2089C>T | NP_006843.2:p.(Arg697Ter) | – | 0 | 0 | – | – | 39 | Deleterious (77) | 0.92219 | 1.00/5.67 | WT | WT | HET | WT | WT | ||||
| SLC9A9a | NM_173653.4:c.1486G>A | NP_775924.1:(p.Asp496Asn) | rs111291437 | 0.00035727 | 0.000599042 | 0.001 | 0.0009185 | 23.7 | Deleterious (82) | 0.87253 | 0.0/−0.25 | HET | WT | HET | HET | HET | ||||
| F21 | UM | UF | P (M) | |||||||||||||||||
| GNB4 | NM_021629.4:c.668C>T | NP_067642.1:p.(Tyr223Met) | rs144385061 | 0 | 0.000399361 | 0.0002 | 0.0001423 | 24.5 | Deleterious (87) | 0.96820 | 0.63/1.90 | HET | HET | HOM | ||||||
| SPAG5a | NM_006461.4:c.3049C>T | NP_006452.3:p.(Gln1017Ter) | – | 0 | 0 | – | – | 36 | Deleterious (57) | 0.81069 | 0.0/0.08 | WT | HET | HET | ||||||
| DOPEY2/DOP1Ba | NC_000021.8(NM_005128.3):c.2775 + 5G>C | – | – | 0.002522068 | 0 | – | – | 15.00 | Deleterious (97) | 0.99276 | 0.0/0.22 | HET | HET | HOM | ||||||
| F22 | UM | UF | P (M) | AS (M) | AS (M) | AS (M) | ||||||||||||||
| HEATR1 | NM_018072.6:c.3803C>T | NP_060542.4:p.(Pro1268Leu) | – | 0.000840689 | 0 | – | – | 24.0 | Deleterious (87) | 0.94516 | 1.00/−1.13 | WT | HET | HET | WT | WT | HET | |||
| F24 | No candidate variants found | |||||||||||||||||||
| F25 | UM | UF | P (M) | AS (M) | AS (M) | AS (F)c | US (M) | US (M) | ||||||||||||
| PSRC1 | NM_001032291.2:c.919C>T | NP_001027462.1:p.(Arg307Ter) | – | 0.000840689 | 0 | 8.60E−06 | 1.29E−05 | 36 | Neutral (91) | 0.08066 | 0.0/0.09 | HET | WT | HET | HET | HET | HET | HET | WT | |
| KIF21Aa | NM_001173463.2:c.4324C>G | NP_001166934.1:p.(Leu1442Val) | – | 0.000250627 | 0 | 8.24E−06 | 6.50E−06 | 25.9 | Deleterious (87) | 0.99321 | 0.0/1.12 | HET | WT | HET | WT | HET | HET | HET | WT | |
In bold are individuals whom samples underwent WES trio analysis.
PredticSNP2 predictions were reported with the expected accuracy (%).
Genomic, transcript, and protein reference sequence identifiers are from NCBI database (GRCh37/hg19).
All NGS files were deposited in the SHGP repository [https://genomics.saudigenomeprogram.org/en/].
Variants LOVD IDs and other information are listed in Table S11.
P proband, UM unaffected mother, AS affected sibling, UF unaffected father, US Unaffected sibling, 1000G 1000 Genomes, SHGPdb Saudi human genome program database.
aMouse model(s) with behavioral and/or neurological phenotype has been documented for this gene in Mouse Genome Informatics database [http://www.informatics.jax.org], for details see Table S7.
bThe same variant was detected in a homozygous state in one ASD case (unpublished data).
cSuspected ADHD case.