Table 1.
Clinical features and model organism phenotypes for genes implicated in histone H2A ubiquitin remodeling and neurodevelopmental disorders.
| Gene/Disorder | Human Phenotypes | pLI* | Z score# | Model system/reported phenotypes | References |
|---|---|---|---|---|---|
| ASXL1/BOS | Developmental delays, ID, hypotonia, Hypoplastic/agenesis corpus callosum, delayed myelination, microcephaly, craniofacial dysmorphisms, feeding difficulties skeletal manifestations, VSD, ASD | 0.00 | 0.08 | Mouse/Craniofacial dysmorphism, skeletal transformations, myeloid dysplasia | [79, 96] |
| ASXL2/SPS | Delayed physcomotor development and speech, ID, ventriculomegaly, white matter volume loss, enlarged extra axial spaces, macrocephaly craniofacial dysmorphisms, feeding difficulties, skeletal manifestations, ASD | 0.99 | −0.01 | Mouse/Abnormal Heart morphology, skeletal transformations | [74] |
| ASXL3/BRS, Autism | Global psychomotor development delay, profound ID, microcephaly craniofacial dysmorphisms- feeding difficulties, skeletal manifestations | 1.00 | −0.94 | NA | [5] |
| USP16/Down Syndrome | ID, ventriculomegaly, Hypotonia, Skeletal manifestations, CHD, AVC | 0.01 | −0.89 | Mouse - Embryonic lethal < E7.5 Xenopus laevis-homeotic transformation |
[21, 62] |
| AUTS2/Autism | Delayed physcomotor development and speech, learning difficulties, microcephaly, ID, hypertonia, craniofacial dysmorphisms, feeding difficulties, skeletal manifestations | 1.00 | 3.09 | Mouse - developmental delay in sensorimotor, cognition and communication Zebrafish - craniofacial dysmorphism |
[4, 44] |
| PHC1/Microcephaly | Low-normal intelligence, microcephaly, craniofacial dysmorphisms- | 1.00 | 4.01 | Mouse - Congenital heart defects, homeotic transformations, craniofacial dysmorphisms | [39, 44] |
| TRIM37/Mulibrey Nanism | Large cerebral ventricles and cisternae, dysarthria, craniofacial dysmorphisms, dolichocephaly, skeletal manifestations, myocardial fibrosis, congestive heart failure, pericardial constriction, globular shaped heart | 0.17 | 1.42 | Mouse - cardiomyopathy, reproductive organ defects | [52] |
| BCOR/Syndromic Microphthalmia 2 | Mild ID, delayed motor development, hypoplastic or absent optic chiasm, spastic paraparesis, hypoplastic corpus callosum, microcephaly craniofacial dysmorphisms-Skeletal manifestations, ASD, VSD, Aortic valve stenosis, pulmonary valve stenosis, pentalogy of fallot, DORV, Dextrocardia, mitral valve prolapse, tricuspid valve inefficiency | 1.00 | 1.06 | Mouse - Heart defects, craniofacial dysmorphism, abnormal forebrain development, decreased cerebellar size | [59] |
ASD = Atrial septal defects, AVC = Atrioventricular canal, BOS = Bohring Opitz Syndrome, BRS = Bainbridge Ropers Syndrome, CHD = Congenital heart disease, SPS = Shashi-Pena Syndrome VSD = Ventricular septal defect
Both Zscore and pLI values have been obtained from the ExAC browser (http://exac.broadinstitute.org).
pLI is the probability of being loss-of-function (LoF) intolerant (pLI). The closer pLI is to one, the more LoF intolerant the gene appears to be.
for synonymous and missense Z score has been created. Z score is the deviation of observed counts from the expected number.
Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer variants than expected. Negative Z scores are given to genes that had more variants than expected.