Table 1.
Phenotype characteristics of individuals with loss of function variants in ZNF462
| Patient | Age | Sex | ZNF462 variant (NM_021224.5) | Inheritance | DD | ASD | Ptosis | Down slanting palpebral fissures | Arched eyebrows | Short upturned nose with bulbous tip | Exaggerated cupid bow/wide philtrum | Feeding issues | Epicanthal folds | Ears | Craniosynostosis /metopic ridging | Hypotonia | Hypertelorism | Corpus callosum dysgenesis | CHD | Limb anomalies (minor) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 16m | M | c.2590C>T p.(Arg864*) | maternal (mosaic) | motor/speech | − | + | − | + | − | + | + | + | low set | − | + | + | normal MRI | not reported | fifth finger clinodactyly |
| 2 | 10y | M | c.2542del p.(Cys848Valfs*66) | de novo | motor/speech | + | + | + | + | + | + | + | + | − | − | − | + | normal MRI | not reported | not reported |
| 3 | 6y | M | c.831_834del p.(Arg277Serfs*26) | de novo | motor/speech | − | − | − | − | + | − | + | − | inner ear malformation | − | + | + | normal MRI | bicuspid aoritc valve; VSD | not reported |
| 4 | 2y 7m | M | c.6214_6215del p.(His2072Tyrfs*8) | de novo | speech | − | + | − | − | − | + | + | + | small, lowset | + | − | − | not tested | not reported | not reported |
| 5 | 14y | F | c.763C>T p.(Arg255*) | paternal | IEP/special education | − | + | − | + | − | − | − | + | hearing loss | + | − | − | not tested | not reported | not reported |
| 6 | 7m | F | c.7057–2A>G | de novo | early intervention for DD | − | + | + | + | + | + | + | + | horizontal crus helix | − | + | + | normal MRI | VSD | prominent creases on hands and feet |
| 7 | 13y | M | c.6794dup p.(Tyr2265*) | de novo | cognitive impairment | + | − | − | + | − | + | − | − | prominent ears/ear pits/hearing loss | + | − | − | not tested | not reported | not reported |
| 8 | 2y | M | c.882dup p.(Ser295Glnfs*64) | de novo | speech delay | − | + | + | − | − | − | − | − | − | − | − | − | ACC | not reported | not reported |
| 9 | 15y | M | c.4165C>T p.(Gln1389*) | de novo | global | − | + | + | + | − | + | + | − | lowset | − | + | − | not tested | not reported | not reported |
| 10 | 8y | M | c.1234_1235insAA; p.(Ser412*) | unknown | speech delay; motor apraxia; IEP | − | + | − | − | − | − | + | mildly cupped ears | − | − | − | normal MRI | not reported | not reported | |
| 11 | 2 y 5 m | F | c.6214_6215del p.(His2072Tyrfs*8) | de novo | − | − | + | − | − | − | − | + | − | + | − | not tested | not reported | not reported | ||
| 12 | 9m | M | c.2049dup p.(Pro684Serfs*14) | de novo | motor | − | + | + | + | + | + | − | + | − | − | + | + | normal MRI | not reported | not reported |
| 13 | 8y 7m | M | c.6631del p.(Arg2211Glyfs*59) | de novo | − | − | + | + | − | + | + | − | − | − | − | − | + | not tested | not reported | 5th finger clinodactyly |
| 14 | 8y | F | c.2695G>T; p.(Glu899*) | mother negative/father unknown | cognitive impairment | − | − | − | + | − | − | + | − | − | − | + | − | normal MRI | not reported | not reported |
| 15a | 2y | F | c.3787C>T p.(Arg1263*) | paternal | − | − | + | + | + | + | + | not reported | − | − | + | − | + | ACC; colpocephaly | not reported | not reported |
| 16a | 4y | F | c.3787C>T p.(Arg1263*) | paternal | − | − | + | + | − | + | + | not reported | + | − | + | − | − | normal prenatal ultrasound | not reported | not reported |
| 17a | 34y | M | c.3787C>T p.(Arg1263*) | maternal | − | − | + | − | − | − | − | not reported | − | − | + | − | − | not tested | not reported | not reported |
| 18a | 2y | M | c.2979_2980delinsA p.(Val994Trpfs*147) | de novo | speech | + | + | + | + | + | − | + | + | left overfolded ear | + | − | − | − normal MRI | not reported | single palmar crease ;5th finger clinodactyly |
| 19a | 32m | M | c.4263del p.(Glu1422Serfs*6) | de novo | motor/speech | + | + | + | − | + | − | − | + | lowset | + | + | + | hypoplastic corpus callosum and ventriculomegaly | D-TGA | not reported |
| 20a | 5y | F | Chr9:g.(108940763–110561397)del (hg19) | de novo | − | − | + | + | + | + | + | not reported | + | − | + | − | hypoplastic corpus callosum | not tested | not reported | |
| 21a | 15y | F | Chr9:g(108464368–110362345)del (hg19) | de novo | motor/intellectual | + | − | − | − | − | + | not reported | − | − | − | + | not tested | VSD | not reported | |
| 22a | 9y | M | c.5145delC p.(Tyr1716Thrfs*28) | de novo | motor/speech delay | + | + | − | − | − | − | not reported | − | − | − | + | − | normal MRI | not reported | not reported |
| 23b | 5y | F | t(2;9)(p24;q32); disrupting ZNF462 and ASXL2 | de novo | intellectual disability | + | + | + | + | + | + | + | − | lowset; hearing loss | − | + | − | ACC; dilated venricles | VSD; left ventricular hypertrophy | single palmar crease; hypoplastic finger nails |
| 24c | 24y | M | t(9; 13)(q31.2; q22.1) disrupting ZNF462 and KLF12 | de novo | intellectual disability | + | + | + | − | − | − | + | + | lowset | + | + | − | hypoplastic corpus callosum | none reported | small hands and feet; proximally placed thumbs |
| Cohort prevalenced | 79% | 33% | 83% | 58% | 50% | 46% | 54% | 50% | 46% | 50% | 38% | 50% | 25% | 25% | 21% | 25% | ||||
d
In order to avoid overestimating phenotype prevalence, we divided each positive phenotype report by the entire cohort (n=24).
Abbreviations: ACC (agenesis of the corpus callosum); ASD (autism spectrum disorder); CHD (congenital heart disease); DD (developmental delay); D-TGA (D-transposition of the great arteries); F (female); IEP (individualized education program); M (male); MRI (magnetic resonance imaging); ventricular septal defect (VSD);