Table 1: OMIM genes constrained by shet but not by LOEUF.
Mutations that disrupt the functions of these genes are associated with Mendelian diseases in the OMIM database [36]. Genes are ordered by shet (posterior mean). Obs. and Exp. are the unique number of observed and expected LOFs respectively. *RPS15A is associated with Diamond-Blackfan anemia along with 12 other genes considered constrained by shet but not by LOEUF (Supplementary Table 1), with 9 of the 12 genes falling outside the most constrained quartile by LOEUF. These genes were chosen from 301 genes that had shet > 0.1 but were not in the most constrained LOEUF quartile. This includes 71 of 3,045 genes with pathogenic ClinVar variants that fall outside the most constrained LOEUF quartile.
| Gene | s het | LOEUF | Obs. | Exp. | Condition and reference |
|---|---|---|---|---|---|
| RPS15A* | 0.68 | 0.56 | 0 | 5.4 | Diamond-Blackfan anemia: Red blood cell aplasia resulting in growth, craniofacial, and other congenital defects [23] |
| DCX | 0.28 | 0.62 | 3 | 12.6 | Lissencephaly: Migrational arrest of neurons resulting in mental retardation and seizures [24] |
| UBE2A | 0.28 | 0.54 | 0 | 5.6 | Intellectual disorder, Nascimento type: Intellectual disability characterized by dysmorphic features [25] |
| PQBP1 | 0.28 | 0.50 | 1 | 9.5 | Renpenning syndrome: Mental retardation with short stature and a small head size [26] |
| NAA10 | 0.28 | 0.52 | 1 | 9.1 | Syndromic microphthalmia: Missing or abnormally small eyes from birth [27] |
| SOX3 | 0.22 | 0.86 | 1 | 5.5 | Intellectual disorder and isolated growth hormone deficiency: Impaired fetal growth and intellectual development [28] |
| NDP | 0.20 | 0.88 | 0 | 3.4 | Norrie disease: Retinal dystrophy resulting in early childhood blindness, mental disorders, and deafness [20] |
| EIF5A | 0.19 | 0.54 | 1 | 8.7 | Faundes-Banka syndrome: Developmental delay, microcephaly, and facial dysmorphisms [29] |
| CDKN1C | 0.19 | 0.53 | 0 | 5.7 | Beckwith-Wiedemann syndrome: Pediatric overgrowth with predisposition to tumor development [30] |
| BCAP31 | 0.15 | 0.65 | 2 | 9.7 | Deafness, dystonia, and cerebral hypomyelination Motor and intellectual disabilities, with deafness and involuntary muscle contraction [31] |
| SOX2 | 0.14 | 0.57 | 1 | 8.3 | Syndromic microphthalmia: Missing or abnormally small eyes from birth [32] |
| SH2D1A | 0.14 | 0.96 | 1 | 4.9 | Lymphoproliferative syndrome: Immunodeficiency characterized by severe immune dysregulation after viral infection [33] |
| GATA4 | 0.12 | 0.53 | 3 | 14.7 | Atrial septal defect: Congenital heart defect resulting in a hole between the atria [34] |
| TWIST1 | 0.11 | 1.1 | 1 | 4.5 | Saethre-Chotzen syndrome: Craniosynostosis, facial dysmorphism, and hand and foot abnormalities [21] [22] |
| TAFAZZIN | 0.11 | 0.49 | 2 | 13.0 | Barth syndrome: Disorder in lipid metabolism characterized by heart, muscle, immune, and growth defects [35] |