Table 1.
Individuals with TNPO2 variants present with developmental delays, intellectual disability, behavioral deficits, and strabismus
| Summary | Proband |
|||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | ||
| Protein variant (p.) | SNV, del, delins | Gln28Arg | Gln32Arg | Pro61Arg | Lys118Asn | Lys152del, mosaic (16/21%) | Asp156Asn | Trp370Arg | Trp370Cys | Lys491_Arg492delinsGlnTrp | Pro514Leu | Ala546Val | Ser548Phe | Phe598Leu | Ala649_Leu652del | Trp727Cys |
| CADD score | 22.7–34.0 | 27.8 | 24.3 | 23.9 | 22.7 | – | 27.1 | 34.0 | 28.8 | – | 30.0 | 27.0 | 31.0 | 29.4 | – | 25.5 |
| Sanger confirmed? | 10 of 15 | yes | yes | – | yes | yes | – | yes | yes | yes | – | yes | – | yes | – | yes |
| Inheritance | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | mother, mosaic (1%) | de novo | de novo |
| Additional variants of uncertain significance | 6 of 15 | – | – | – | – | SETBP1:p.Leu1522Argfs∗59; CUX2: p.His1253Pro; 12q13.13_dup | ANKFY1: p.Thr1088Serfs∗9 | – | ARMC9: p.Asp330Asn | – | 1q21.1_ins522Kb | – | – | – | PDE4D: p.Arg237∗ | INA p.Leu376Pro, mosaic (20%) |
| Age at onset | neo-18mo | 1mo | 4mo | neonat. | 13mo | 3mo | 6mo | 4mo | neonatal | prenatal | 9mo | 8mo | neonat. | 15mo | 18mo | neonat. |
| Age at exam | 14mo-20y | 6y | 18mo | 6mo | 3y | 23mo | 4y | 10y | 8y | 14mo | 5y | 9y | 20y | 11y | 12y | 7y |
| Global developmental delays | 15 of 15 | ++ | +, regress. | + | ++, regress. | +++ | ++ | +++ | + | + | ++ | + | +++ | +, regress. | + | ++ |
| Speech impaired | 15 of 15 | ++ | + | + | ++ | +++ | +++ | +++ | + | + | ++ | + | +++ | + | + | ++ |
| Intellectual disability | 9 of 9 | +++ | ND | ND | +++ | ND | ++ | +++ | ++ | ND | ND | ++ | +++ | + | ++ | ND |
| Motor Impaired | 15 of 15 | + | + | + | ++ | +++ | ++ | +++ | + | + | + | + | +++ | + | + | + |
| Dysmorphic features | 11 of 15 | + | – | + | + | – | + | – | + | + | + | – | + | + | + | + |
| Behavioral deficits | 10 of 14 | + | + | + | + | – | + | – | + | – | – | + | ND | + | + | + |
| GI / feeding abnormalities | 11 of 15 | + | + | + | – | + | – | + | + | – | + | – | + | + | + | + |
| Ophthalmologic abnormalities | 10 of 15 | + | – | – | + | + | + | – | + | + | + | + | – | + | – | + |
| Muscle tone abnormalities | 11 of 15 | +, hypo | – | +, hypo | – | +, hypo | +, variable | +, hypo | – | +, hypo | +, variable | – | +, hypo | +, hypo | +, hypo | +, hyper |
| Movement /neurological disorder | 6 of 15 | + | – | – | – | + | + | – | – | – | – | + | + | + | – | - |
| Seizures | 6 of 15 | +, febrile | – | – | – | – | +, febrile to non-febrile | +, febrile to non-febrile | – | – | +, febrile to non-febrile | +, febrile to non-febrile | + | – | – | – |
| Microcephaly | 5 of 15 | + | – | – | + | + | + | – | – | + | – | – | – | – | – | – |
| MRI brain abnormalities | 7 of 13 | – | ND | + | – | + | + | – | + | + | + | – | + | – | ND | – |
misZ for TNPO2 loss is 5.88 (o/e = 0.28). pLI for TNPO2 loss is 1.00 (o/e = 0.04). TNPO2 coding DNA (GenBank: NM_001136196.1). All individuals are heterozygous for variants. No variants are found in control genetic databases. See Data S1 and Note S1 for additional details on probands’ features and additional variants of uncertain significance. ND, no data; CADD, combined annotation dependent depletion.