Table 3.
Nucleotide variants conferring susceptibility for autism (stratified by category) identified among the 253 ASD subjects. Nucleotide variants in genes harboring a statistically significant excess of de novo PTVs were classified either as susceptibility variants in class A genes (false discovery rate (FDR) <5%) or as probable susceptibility variants in class B genes (10% < FDR < 5%). Nucleotide variants in syndromic ASD–related genes were classified using the guidelines from the American College of Medical Genetics-Association for Molecular Pathology.
| ID | Gene | Variation | Transcript | Inheritance | o/e | GnAD | Diag | Age | Sex | Family history |
|---|---|---|---|---|---|---|---|---|---|---|
| (a) Nucleotide variants in genes harboring a statistically significant excess of de novo PTVs | ||||||||||
| Susceptibility variants | ||||||||||
| 213 | CHD8 | p.Gln1171* c.3511C>T | NM_001170629.1 | Paternal | 3.94% | _ | ASD+ID | 7 | F | S |
| 223 | CHD8 | p.Lys528Glyfs*14 c.1582_1583delAA | NM_001170629.1 | DN | 3.94% | _ | Asperger | 19 | M | S |
| 220 | CHD8 | p.Leu980Argfs*5 c.2937_2939delinsTC | NM_001170629.1 | DN | 3.94% | _ | Asperger | 30 | M | S |
| 98 | NRXN1 | p.Leu158Alafs*29 c.471dupG | NM_001135659.1 | DN | 12.30% | 1/242 430 | Asperger | 12 | M | S |
| 307 | NRXN1 | p.Glu389Serfs*3 c.1165delG | NM_001135659.1 | Maternal | 12.30% | _ | ASD | 3 | M | S |
| 253 | ANK2 | p.Glu3062* c.9184G>T | NM_001148.4 | DN | 6.20% | _ | Asperger | 11 | M | S |
| 325 | GIGYF1 | p.Ter1036Glyext*72 c.3106T>G | NM_022574.4 | DN | 35.64% | _ | ASD | 12 | M | Faa |
| 341 | KDM5B | p.Arg1397* c.4189C>T | NM_006618.4 | NA | 44.95% | 2/247 406 | ASD | 4 | M | S |
| Probable susceptibility variants | ||||||||||
| 122 | RIMS1 | p. ? c.100+1G>A | NM_001168407.1 | Maternal | 18.65% | 1/31 404 | ASD+ID | 14 | F | S |
| 188 | SETD2 | p.Arg1708* c.5122C>T | NM_014159.6 | DN | 13% | _ | Asperger | 8 | F | Fab |
| 301 | DIP2A | p. ? c.1429+2T>G | NM_015151.3 | Maternal | 23.89% | _ | Asperger | 6 | F | S |
| 285 | HECTD4 | p.Ala3108Glyfs*5 c.9322dupG | NM_001109662.3 | Maternal | 7.56% | _ | Asperger | 12 | M | S |
| 168 | SPEN | p.Ser2411* c.7232C>A | NM_015001.2 | DN | 2.31% | _ | Asperger | 6 | M | S |
| (b) Nucleotide variants in syndromic ASD-related genes | ||||||||||
| Susceptibility variants | ||||||||||
| 370 | EBF3 | p.Gln78* c.232C>T | NM_001005463.2 | DN | 3% | _ | ASD | 4 | M | S |
| 79 | TSC2 | p.Val1062Glyfs*7 c.3185_3188del | NM_000548.3 | DN | 2% | _ | ASD+ID | 8 | F | S |
| Probable susceptibility variants | ||||||||||
| 30 | DEAF1 | p.Arg224Gln c.671G>Ac | NM_021008.3 | Maternal | 41% | 1/246 022 | ASD+ID | 14 | M | S |
| 328 | DNMT3A | p.Gln249* c.745C>T | NM_022552.4 | DN | 126% | 1/244 420 | ASD+ID | 10 | M | S |
| 215 | AUTS2 | p.Thr328Argfs*19 c.983_984del | NM_015570.3 | DN | 13% | _ | ASD+ID | 4 | M | S |
| 222 | DYNC1H1 | p.? c.4396–1G>C | NM_001376.4 | DN | 5% | _ | ASD | 27 | F | Faa |
| 121 | NR2F1 | p.Gly395Ala c.1184G>C | NM_005654.5 | DN | 0.00% | _ | ASD+ID | 20 | M | S |
| (c) Nucleotide variants in genes belonging to both categories | ||||||||||
| Susceptibility variants | ||||||||||
| 296 | SHANK3 | p.Pro922Argfs*34 c.2765del | NM_033517.1 | DN | 3.98% | _ | ASD+ID | 8 | F | S |
| 377 | SHANK3 | p.Leu1030Cysfs*48 c.3088delC | NM_033517.1 | DN | 3.98% | _ | ASD+ID | 6 | M | S |
| 353 | SHANK3 | p.Ala1227Glyfs*69 c.3679dupGd | NM_033517.1 | NA | 3.98% | _ | ASD+ID | 31 | F | S |
| 136 | GRIN2B | p.Ser9Phefs*50 c.23_24insC | NM_000834.3 | DN | 0.00% | _ | ASD | 4 | M | S |
| 85 | ASXL3 | p.Ser1246* c.3737C>A | NM_030632.1 | DN | 9.86% | _ | ASD+ID | 11 | M | Fa |
| 78 | SCN2A | p.Phe601Leufs*40 c.1800delC | NM_001040142.1 | DN | 6.33% | _ | ASD+ID | 12 | F | S |
| 382 | CHD2 | p.Val332Glyfs*25 c.995_999delTGAAG | NM_001271.3 | NA | 2.75% | _ | ASD+ID | 7 | M | S |
| 47 | DYRK1A | p.Arg255* c.763C>Te | NM_101395.2 | Not maternal | 8.45% | _ | ASD+ID | 18 | M | S |
| 395 | ANKRD11 | p.Glu1154Glyfs*16 c.3460dup | NM_001256182.1 | DN | 4.72% | _ | Asperger | 11 | M | S |
| Probable susceptibility variants | ||||||||||
| 291 | KMT2A | p. ? c.10835+1G>Af | NM_001197104 | Paternal | 3.12% | _ | Asperger | 6 | M | S |
| 324 | KMT2A | p.Gln3192Pro c.9575A>C | NM_001197104 | DN | 3.12% | _ | ASD | 9 | M | S |
| 157 | MECP2 | p.Glu282Gly c.845A>G | NM _004992.3 | DN | 10.72% | _ | ASD | 13 | F | S |
F female, M male, S sporadic, Fa familial, DN de novo, NA not assessed, o/e observed/expected ratio of PTVs in GnomAD, GnAD allelic frequency in the GnomAD database.
aSib (ASD): wild type.
bSib (Asperger): wild type.
cp.Arg224Trp found as a de novo event in an ASD case27.
dVariation found as de novo event in ASD+ID cases28.
eVariation found as a de novo event in a syndromic case of DYRK1A-haploinsufficiency29.
fVariation found in three related ID patients14..