Table 2.
Summary of results for the 11 candidate variants detected by WES in 19 female ID patients with extreme skewing
| Patient number | XCI pattern | Gene |
Location | Type of variant |
Variant | Inheritance |
NGS-Logistics |
XCI pattern mother | PhyloP SIFT PolyPhen2 LRT MutationTaster |
On Xa or Xi? | Escape? Carrel et al 2005) |
Major clinical features |
Remarks |
||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Candidate causes XLID | and skewing | 1 | 99 mat | DDX3X | X:41203531 | ns |
NM_001193417.2: c.856G>A:p.G286S |
likely de novo | 0/1115 | 78 | C / D D / | ? | 9/9 | Severe ID, ataxic gait, cleft uvula, facial dysmorphism, vesicoureteric reflux |
|
| 2 | 92 pat | DDX3X | X:41202502 | stop |
NM_001193417.2: c.529G>T:p.G177X |
de novo | 0/734 | 52 | C / / D / | ? | 9/9 | Mild to moderate ID, pre- and postnatal growth restriction, hirsutism, hypertelorism, facial features, hallux valgus with foot arches |
|||
| 3 | 93 pat | SMC1A | X:53430567 | ns |
NM_006306.3: c.2351T>C:p.I784T |
de novo | 0/870 | 76 | C D D D D | Xi | 7/9 | Severe psychomotor delay, intrauterine and postnatal growth restriction, synophrys, hirsutism, dysmorphism, microcephaly, hypertonia, congenital heart anomalies, gastroesophageal reflux, hearing loss, hallux valgus, talus valgus, dysplastic nails |
2 female ID patients with skewing and same variant (Gervasini et al. 2013; Limongelli et al. 2010) |
||
| 4 | 93 mat | WDR45 | X:48933072 | fr del |
NM_001029896.1: c.777delT:p.T260Lfs*27 |
de novo | 0/? | 81 | / / / / / | Xa | 0/9 | Severe ID, progressive spasticity, short stature (145 cm at 29 years) |
|||
| 5 | 95 mat | NHS | X:17705990 | stop |
NM_001136024.3: c.163C>T:p.Q55X |
de novo | 0/836 | 72 | C / / D A | ? | 3/9 | Mild ID, ASD, congenital cataract microphthalmia, abnormal teeth |
|||
| 6 | 94 ? | MECP2 | X:153296399 | stop |
NM_004992.3: c.880C>T:p.R294X |
0/801 | C / / D / | ? | 0/9 | Severe ID, spastic quadriplegia, microcephaly (OFC – 3.3) |
rs61751362 | ||||
| Candidate causes skewing |
7 | 98 mat | MED12 | X:70343021 | ns |
NM_005120.2: c.1562G>A:p.R521H |
de novo | 0/811 | 79 | C D D D D | Xi | 0/9 | Severe ID, ASD | ||
| 8 | 93 mat | HDAC8 | X:71681901 | ns |
NM_018486.2: c.958G>A:p.G320R |
de novo | 0/711 | 87 | C D P D D | Xi | NR | Moderate ID, postnatal growth restriction, hypotonia, seizures, autistic traits |
male patient with same variant (Deardorff et al. 2012) |
||
| Candidate causes autosomal ID |
9 | 96 ? | EP300 | 22:41574281 | in-frame del |
NM_001429.3: c.6567_6578del:p.2189_2193del |
0/? | / / / / / | ? | / | Mild developmental delay, hearing disability, relative microcephaly, dysmorphism |
||||
| Candidate causes skewing |
10 | 93 ? |
SYNGAP1 TAF9B |
6: 33412306 X:77392414 |
ns indel affecting splicing |
NM_006772.2: c.3494C>T:p.S1165L NG_012570.1:g.7766_7770delinsAA |
0/802 0/? |
? | C T D D D / / / / / |
? | / 0/9 |
Nonsyndromic mild to moderate ID, schizophrenia |
|||
X-linked genes are indicated in bold; ID: intellectual disability; XCI: X chromosome inactivation; mat/pat: maternally/paternally inherited predominantly inactivated X chromosome; XLID: X-linked ID; NR: not reported; ns: nonsynonymous; fr: frameshift; del: deletion; ins: insertion; stop: stop variant; C: conserved; /: not applicable; D: damaging/deleterious/disease causing; T: tolerated; P: possibly damaging; A: disease automatic; Xi: inactive X; Xa: active X; ASD: autism spectrum disorder; OFC: occipitofrontal head circumference