Table 2: Causative variants found in the 150 patient cohort.
For maternally inherited variants, based on X-inactivation analysis, the quote of expressed mutated allele in the mother was reported. Prediction consensus is calculated among the twelve methods provided by ANNOVAR (see Methods section). Variant interpretation based on InterVar: criteria manually adjusted based on our findings (Richards et al. 2015).
| Patient | Sex | Gene | Mutation | Mode of inheritance | Variant segregation | dbSNP | gnomAD AC/AN | Prediction consensus | CADD | Correlation with classic phenotype | InterVar manually adjusted (criteria) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 2033.01 | M | ANKRD11 | chr16:89345974CCTTCGGGG>C; NM_013275.5:c.6968_6975del; p.Ala2323Glyfs*206 | AD | de novo | _ | _ | _ | _ | Yes | Pathogenic (PVS1, PM2, PM4, PM6, PP4) |
| 2338.01 | F | ANKRD11 | chr16:89346136CAG>C; NM_013275.5:c.6812_6813del; p.Pro2271Argfs*24 | AD | _ | _ | _ | _ | _ | Yes | Pathogenic (PVS1, PM2, PP4) |
| 2127.01 | F | ARID1B | chr6:157528165G>T; NM_017519.2:c.5851G>T; p.Glu1951* | AD | de novo | _ | _ | _ | _ | Yes | Pathogenic (PVS1, PM2, PM6, PP3, PP4) |
| 2276.01 | M | ATRX | chrX:76909661T>C; NM_000489.4:c.4244A>G; p.Asn1415Ser | XLR | Maternal, random 60% | rs782562458 | 1/177812 | 9/12 | 23 | Partially | Likely pathogenic (PS2, PM2, PP3, PP6) |
| 602.01 | F | CASK | chrX:41401980G>A; NM_003688.3:c.2119C>T; p.Gln707* | XLD | de novo | _ | _ | _ | _ | Yes | Pathogenic (PS2, PV1, PM2, PP3) |
| 196.01 | M | CASK | chrX:41448842A>G; NM_003688.3:c.1159T>C; p.Tyr387His | XLD | de novo | _ | _ | 5/12 | 20.8 | Partially | Likely pathogenic (PM1, PM2, PP3) |
| 2222.01 | M | DYRK1A | chr21:38858777G>C; NM_001396.4:c.525G>C; p.Lys175Asn | AD | de novo | _ | _ | 8/12 | 25.8 | Yes | Pathogenic (PS2, PM1, PM2, PP3, PP4) |
| 2166.01 | M | EHMT1 | chr9:140728837G>C; NM_024757.4:c.3577G>C; p.Gly1193Arg | AD | de novo | _ | _ | 11/12 | 34 | Yes † | Likely pathogenic (PM1, PM2, PM6, PP3, BP1) |
| 2243.01 | M | EHMT1 | chr9:140657209GA>G; NM_024757.4:c.1585del; p.Ser529Valfs*34 | AD | de novo | _ | _ | _ | _ | Yes | Pathogenic (PVS1, PS2, PM2, PM4, PP4) |
| 2140.01 | M | GRIA3 | chrX:122460015G>A; NM_000828.4:c.647G>A; p.Arg216Gln | XLR | Maternal affected, Skewed 74% | rs753214982 | 8/199967 | 7/12 | 23.3 | Yes | Likely pathogenic (PM1, PM2, PP3, PP6) |
| 2278.01 | M | GRIN2B | chr12:13761626T>G; NM_000834.4:c.1921A>C; p.Ile641Leu | AD | de novo | _ | _ | 7/12 | 28.6 | Yes | Likely pathogenic (PM1, PM2, PM6) |
| 2019.01 | M | GRIN2B | chr12:13724822C>T; NM_000834.4:c.2087G>A; p.Arg696His | AD | de novo | _ | _ | 6/12 | 35 | Yes ‡ | Pathogenic (PS2, PM1, PM2, PP3, PP6) |
| 2145.01 | F | MECP2 | chrX:153296399G>A; NM_004992.3:c.880C>T; p.Arg294* | XLD | de novo | rs61751362 | 3/183432 (1 Hem) | _ | _ | Yes | Pathogenic (PVS1, PS2, PS4, PM2, PP2, PP3, PP4, PP5) |
| 414.01 | F | MECP2 | chrX:153296777G>A; NM_004992.3:c.502C>T; p.Arg168* | XLD | _ | rs61748421 | _ | _ | _ | Yes | Pathogenic (PVS1, PS4, PM2, PP3, PP4, PP5) |
| 1730.01 | F | OPHN1 | chrX:67273488C>T; NM_002547.2:c.2323G>A; p.Val775Met | XLR | de novo | _ | _ | 6/12 | 24.3 | Yes | Likely pathogenic (PM2, PM6, PP3, PP4) |
| 1974.01 | M | RAB39B | chrX:154490151A>C; NM_171998.2:c.579T>G; p.Phe193Leu | XLR | maternal affected, random 34% | rs782042596 | 2/183440 (2 Hem) | 3/12 | 8.86 | Partially | Uncertain significance (PM1, PM2, PP4) |
| 1985.01 | M | SATB2 | chr2:200213882G>A; NM_001172509.1:c.715C>T; p.Arg239* | AD | de novo | rs137853127 | _ | _ | _ | Yes | Pathogenic (PVS1, PS2, PM2, PP3, PP5) |
| 2274.01 | M | SETBP1 | chr18:42531498AAGAGC:A; NM_015559.2:c.2199_2203del; p.Glu734Alafs*18 | AD | de novo | _ | _ | _ | _ | Yes | Pathogenic (PVS1, PS2, PS4, PP3) |
| 1970.01 | F | SHANK3 | chr22:51159830A>TTC; NM_033517.1:c.[3568_3569insTT;3569A>C]; p.Asp1190Valfs*5 | AD | de novo | _ | _ | _ | _ | Yes | Likely pathogenic (PM2, PM4, PM6, PP4) |
| 2230.01 | F | SHANK3 | chr22:51153476G>A; NM_033517.1:c.2265+1G>A | AD | de novo | _ | 1/158210 | _ | _ | Yes § | Pathogenic (PVS1, PM2, PM6, PP3, PP4) |
| 2271.01 | M | SHANK3 | chr22:51159718C>T; NM_033517.1:c.3457C>T; p.Arg1153* | AD | de novo | _ | _ | _ | _ | Yes | Pathogenic (PVS1, PM2, PM6, PP4) |
| 1749.01 | M | SHANK3 | chr22:51160432GA>G; NM_033517.1:c.4172delA; p.Glu1391Aspfs*36 | AD | de novo | _ | _ | _ | _ | Yes | Pathogenic (PVS1, PS2, PM2, PP4) |
| 2233.01 | M | SYNGAP1 | chr6:33411228C>T; NM_006772.2:c.2899C>T; p.Arg967* | AD | de novo | _ | _ | _ | _ | Yes | Pathogenic (PVS1, PS2, PM1, PM2, PP3, PP4) |
| 984.01 | M | TRIO | chr5:14390392C>T; NM_007118.2:c.4111C>T; p.His1371Tyr | AD | de novo | _ | _ | 7/12 | 27 | Partially | Likely pathogenic (PS2, PM1, PM2, PP3) |
| 2165.01 | M | TRIO | chr5:14394159C>T; NM_007118.2:c.4231C>T; p.Arg1411* | AD | maternal, affected | _ | _ | _ | _ | Yes | Pathogenic (PVS1, PM2, PP3, PP4) |
| 2113.01 | M | MED13L | chr12:116445337C>T; NM_015335.4:c.2117G>A; p.Gly706Glu | AD | de novo | rs200257416 | 7/251400 | 5/12 | 20.3 | Yes | Likely pathogenic (PS2, PM7, PP4) |
| ASH1L | chr1:155449342T>C; NM_018489.2:c.3319A>G; p.Ile1107Val | AD | de novo | rs140137038 | 148/282442 | 1/12 | 0.6 | Partially | Uncertain significance (PS2, BP4) |
M, male; F, female; Genomic position on human GRCh37; AD: autosomal dominant; AR: autosomal recessive; XLD: X-linked dominant; XLR: X-linked recessive
†
according to the EHMT1 phenotypic spectrum described in (Blackburn et al. 2017)
‡
This GRIN2B missense mutation has been previously found in a female with a phenotype similar to our case (Swanger et al. 2016).
§
This SHANK3 splicing mutation has been previously reported by (Li et al. 2018). SHANK3 variants named according to the SHANK3 RefSeq mRNA (NM_033517.1) and protein (NP_277052.1) sequence, in which the exon 11 sequence has been corrected.