Table 1.
Individual Clinical Phenotype
| Group 1 Individuals | Group 2 Individuals | |||||||||||
| Patient | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 |
| TRIO variant | ||||||||||||
| Coding change | c.3224C>T | c.3232C>T | c.3232C>T | c.3232C>T | c.3232C>T | c.3232C>G | c.3233G>A | c.3233G>A | c.3239A>T | c.3895G>A | c.4283G>A | c.4283G>A |
| Protein change | p.Thr1075Ile | p.Arg1078Trp | p.Arg1078Trp | p.Arg1078Trp | p.Arg1078Trp | p.Arg1078Gly | p.Arg1078Gln | p.Arg1078Gln | p.Asn1080Ile | p.Glu1299Lys | p.Arg1428Gln | p.Arg1428Gln |
| Domain | spectrin | spectrin | spectrin | spectrin | spectrin | spectrin | spectrin | spectrin | spectrin | GEFD1 | GEFD1 | GEFD1 |
| Inheritance | NR | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo |
| Sex | M | M | M | M | M | M | F | F | F | M | F | F |
| Age last assessment | 15 years | 12 years | 3 years | 4 years | 7 years | 6 years | 19 years | 40 years | 9 years | 20 months | 16 years | 8 years |
| First smile | NR | NR | <36 weeks | 52 weeks | NR | normal | NR | 24 weeks | NR | 12 weeks | 8 weeks | 6 weeks |
| Sitting unsupported | 12 months | NR | NA | 36 months | 36 months | 7 months | 10.5 months | 9 months | 11 months | 9 months | 10 months | 8 months |
| Walking unaided | 30 months | 84 months | NA, crawling | NA | NA | 24 months | 24 months | 36 months | 48–60 months | NA | 22 months | 12 months |
| First words | 66 months | NR | NA | NA | 36 months | NA | 48–60 months | 52 months | NR | 24 months | NR | NR |
| Learning Difficulties | yes; moderate | yes; severe | yes; severe | yes; severe | yes; severe | yes; severe | yes; moderate | yes; severe | yes; severe | yes; moderate | missing level in charts | yes; moderate |
| Language delay: Expression | yes; dysarthria, short sentences | yes; 50 words at 7 years | yes; babble only | yes; babble only | yes; <10 words | yes; severe, sounds only | yes; impaired articulation | yes; short sentences only | yes; non-verbal, uses Makaton | yes; only a few two- syllable words | yes; very talkative | yes; talkative |
| Language delay: Comprehension | yes | yes | yes | yes | yes | yes; comprehension better | yes | yes | yes | yes | yes; unable to read or write | yes |
| OFC | +0.7 SD | +2.9 SD | +2.2 SD | +2.7 SD | +2.8 SD | +3 SD | +2.4 SD | +4.7 SD | +1.8 SD | −3.8 SD | −5.9 SD | “microcephaly” |
| Other genetic variants | NR | 14q21.1 microdeletion | no | no | no | NR | no | NR | no | no | no | maternally inherited 4p microdeletion |
| Reference (patient) | this study | this study | this study | this study | this study | this study | this study | this study | 17 | this study | 17 | this study |
| Variant described in | - | - | - | - | - | - | - | - | 17 | - | 17, 18 | 17, 18 |
| Group 2 Individuals | Truncation Individuals | |||||||||||
| Patient | 13 | 14 | 15 | 16 | 17a (proband) | 17b (father) | 17c (uncle) | 18 | 19 | 20 | 21 | 22 |
| TRIO Variant | ||||||||||||
| Coding change | c.4381C>A | c.4406A>G | c.4382C>T | c.4382C>T | c.4466delA | c.4466delA | c.4466delA | c.2302C>T | c.4860−2A>G | c.6092dup | c.7050del | c.7461del |
| Protein change | p.Pro1461Thr | p.His1469Arg | p.Pro1461Leu | p.Pro1461Leu | p.Gln1489Argfs∗12 | p.Gln1489Argfs∗12 | p.Gln1489Argfs∗12 | p.Gln768∗ | p.Arg1620Serfs∗10 | p.Leu2031Phefs∗9 | p.Val2351Cysfs∗62 | p.Phe2473Serfs∗54 |
| Domain | GEFD1 | GEFD1 | GEFD1 | GEFD1 | truncating | truncating | truncating | truncating | truncating | truncating | truncating | truncating |
| Inheritance | de novo | de novo | de novo | de novo | inherited | inherited | inherited | NR | de novo | de novo | de novo | NR |
| Sex | F | M | F | F | F | M | M | F | F | M | M | M |
| Age last assessment | 8 years | 14 years | 19 years | 11 years | 17 months | 36 years | 10 years | 14 years | 8 years | 16 years | 9 years | 21 months |
| First smile | 36 weeks | NR | 8 weeks | 28 weeks | NR | NR | NR | NR | NR | 6 weeks | >8 weeks | 21 months |
| Sitting unsupported | 11 months | 9 months | 11 months | 13 months | 9 months | NR | NR | NR | 8 months | 6 months | NR | NA |
| Walking unaided | 30–36 months | 17 months | 21 months | 24 months | 17 months | NR | NR | 14 months | 12 months | 12 months | >24 months | NA |
| First words | 48–60 months | 60 months | NR | 24–36 months | 17 months | NR | NR | 24 months | 10 months | Delayed | >18 months | NA |
| Learning difficulties | yes; global | yes; mild | yes; mild | yes; moderate | yes; mild | yes; mild | yes; mild | yes | yes; mild | yes; severe | yes; moderate | yes; severe |
| Language delay: expression | yes | yes; first sentences at 9 years | yes | yes; literal speech | yes | NR | NR | yes | yes | yes; short sentences | yes | yes; no language development |
| Language delay: comprehension | yes | no | yes | yes | yes | NR | NR | yes | yes | no | yes | yes |
| OFC | −3.8 SD | −4 SD | +1.5 SD | 0.3 SD | −3.3 SD | −2.1 SD | −3.9 SD | −3.5 SD | −4.4 SD | −1.4 SD | +1.4 SD | −4.6 SD |
| Other genetic variants | - | - | no | bi-allelic FAT4 variants regarded as VUS | no | 15q11.2 microdeletion and maternal DM | 15q11.2 microdeletion | no | no | no | 5p15.31 VUS paternally inherited, father phenotypically normal | no |
| Reference (patient) | 17 | this study | this study | this study | 17 | 17 | 17 | this study | this study | this study | this study | this study |
| Variant described in | 17, 18 | - | 18 | 18 | - | - | - | - | - | - | - | - |
Description of the clinical phenotype observed among TRIO mutation carriers, grouped on the basis of variant location or protein effect: spectrin repeat (group 1), GEFD1 (group 2 and p.Pro1461Leu individuals 15 and 16) and protein truncating. Abbreviations are as follows: M, male; F, Female; NR, not recorded; SD, standard deviation; OFC, occipitofrontal circumference; GORD, gastro-esophageal reflux disease; NG, nasogastric; and NA, not achieved.