Table 5.
Categorized CTNNB1 cases according to the severity of the phenotype (n = 35).
| Genetic Mutation | Gender | Age (yrs) | Facial Dysmorphism | Eye Conditions | Microencephaly | Axial Hypotonia/Spasticity | Achieving Milestones | Behavior and IQ | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Exon no. and Variant | Amino Acid Change | Mutation Type | Sitting (mo) | Crawling (mo) | Walking Independently | Speaking | |||||||
| SEVERE PHENOTYPE | |||||||||||||
| I5, c.734 + 1G > T | Splice mutation | Splice | F | 32 | + | Strabismus | + | +/+ | 2–5 years (40mo) | NA | No | Absent speech | Ritualistic behaviours with temper tantrums, autism, severe ID (18 months) |
| I5, c.734 + 1G > A | Splice mutation | Splice | F | 49 | + | FEVR | NA | +/+ | NA | NA | NA | Absent speech | NA, IQ = 40 |
| I5, c.734 + 1G > A | Splice mutation | Splice | F | 27 | + | FEVR | NA | NA | NA | NA | Walking at 49 yrs (ataxic) | Absent speech | NA, IQ = 20 |
| E6, c.755delTinsAAC | p.Leu252* | Nonsense | F | 15.3 | + | Strabismus, hyperopia | - | +/+ | NA | NA | 10 yrs | 2 words | Auto-aggressive behavior, stereotypic movements, short eye contact; severe IQ |
| E6, c.799_809delGAAGGAGCTAAinsGAA | p. Gly268TrpfsTer5 | Frameshift | F | 7 | + | NA | + | +/+ | 18 | NA | 3 (broad based gait) | No speech | Autism, ID |
| MODERATE-SEVERE PHENOTYPE | |||||||||||||
| E4, c.423_424insG | p. Tyr142Valfs*4 | Frameshift | F | 5.6 | + | Strabismus | + | +/- | NA | 24 | not yet | Severe, few words (30), sign language | Repetitive movements, ID |
| E8, c.1163T > C | p.Leu388Pro | Missense | F | 6.8 | + | NA | + | +/+ | 13 | 18 | 2.5 | First word at 2 ½, 20 words at 4 years but not intelligible | ID |
| E9, c.1272_1275del | p.Ser425Thrfs*11 | Frameshift | F | 29 | + | NA | + | +/+ | 24 | 3 years | 8 (progressive spasticity now with support) | Started speaking first words 9–10 years; now able to speak a few words | Aggression, auto-mutilation, and fecal smearing |
| E9, c.1272_1275del | p.Ser425Thrfs*11 | Frameshift | F | 3.25 | + | Strabismus | - | +/+ | NA | NA | not yet | Babbles now, some words are understandable | Very happy and friendly, low frustration tolerance |
| E9, c. 1344_1345 InsertionA | p.Arg449GlnfsTer24 | Frameshift | M | 8 | NA | Strabismus | + | NA/+ | NA | NA | 8 | First words at 3 years, at 8 years able to speak short sentences | Aggression sometimes when frustrated |
| E9, c.1420C > T | p.Arg474* | Nonsense | F | 13 | NA | Strabismus | + | +/+ | N | 13 months | 42 months | First words at 4.5 years | ADHD, aggressive, teeth grinding; mouths objects |
| E9, c.1420C > T | p.Arg474* | Nonsense | F | 5.25 | + | Strabismus | + | +/+ | 18 | 23 | not yet | No words | Stereotypic outbursts |
| E9, c.1543C > T | p.Arg515* | Nonsense | F | 51 | + | Optic atrophy | + | +/+ | NA | NA | No | Not able to speak, but uses sign language | Normal behavior, ID, cognitive abilities gradually deteriorated |
| E10, c.1603C > T | p.Arg535Ter | Nonsense | M | 3.25 | + | Strabismus | + | +/+ | 8 | NA | Unable to walk | Lots of noises but no words | NA |
| E10, c.1603C > T | p.Arg535Ter | Nonsense | M | 14 | + | NA | - | -/+ | 15 | NA | not walking | Moderate; Single words at 14 years | Aggressive outbursts, self-harm |
| E11, c.1801C > T | p.Gln601Ter | Nonsense | M | 6.2 | + | FEVR | + | +/NA | NA | NA | not yet | Says Mom and Dad with understanding, uses Makaton, points to body parts | Occasional temper; can bite others and self; repetitive movements |
| E12, c.1923dupA | p.Glu642Argfs*6 | Frameshift | M | 8.5 | + | Strabismus, hyperopia | + | +/+ | NA | 14 | 8 years | Severe; few single words, gestures | Good social interaction, outburst of temper tantrums or crying, self/biting |
| E12, c.1925_1926del | p.Glu642Valfs*5 | Frameshift | F | 14.2 | + | Strabismus | - | -/+ | not yet | NA | No | Moderate, first words at 6 years; not speaking in sentences | Rages and tantrums, friendly personality, short attention span and poor eye contact; autism |
| MODERATE PHENOTYPE | |||||||||||||
| E3, c.99_100delTG | p.Gly34Asnfs*15 | Frameshift | M | 5.5 | + | Strabismus | + | +/+ | 14; still head-leg | 25 | 6 yrs (cannot stand alone) | Short sentences | Social and friendly boy; no behavioral problems; concentration is limited; sensitive to noises |
| E3, c.232C > T | p.Gln78* | Nonsense | M | 11 | + | Strabismus, hyperopia, astigmatism | - | +/+ | NA | Didn’t crawl | 3 yrs; at 11 yrs coordination problem | Unclear speech; at 11 yrs regression | Temper tantrums, aggression, frustration, anxiety, friendly personality, stereotypic movements |
| E4, c.283C > T | p.Arg95* | Nonsense | F | 4 | + | Normal | + | +/+ | NA | 12 | 4 yrs | Speech apraxia, ~50 words | When young, biting, banging the head in the wall, this has improved now |
| E5, c.705dupA | p.Gly236Argfs*35 | Frameshift | F | 14 | + | Strabismus | + | +/- | 12 | NA | 4.5 yrs | Babbling at 3 yrs, 14 yrs speaking simple sentences, read simple words | Autism, IQ = 65 |
| E7, c.925C > T | p.Gln309* | Nonsense | M | 4.5 | + | Hyperopia | + | +/+ | 18 | NA | walking at 4.6 (short distances) | Started speaking at 4 years, articulation was poor and hard to understand | Happy personality |
| E7, c.998dupA | p.Tyr333Ter | Nonsense | F | 9 | NA | NA | - | +/+ | 14 | NA | 4.2 (still had difficulties) | First words age 4; more fluent speech age 6; said to be 3 years behind with verbal skills | Violent outbursts associated with difficulty expressing emotions |
| E7, c.999C > G | p.Tyr333Ter | Nonsense | F | 27 | + | NA | - | +/+ | 30 | NA | 4.5 (ataxic) | First words at 4.5 years; can speak in sentences but speech very unclear | Aggressive, temper tantrums, self-injurious (biting, picking) |
| E7, c.1038_1044delGCTATCTinsGCT | p.Val349AlafsTer9 | Frameshift | F | 11 | + | Strabismus, hypermetropia | + | +/+ | NA | 13.5 | 3.5 (ataxic) | Single words at age 5 years, talks in sentences at age 11 years | Stereotypies (clapping repeatedly, temper tantrums, aggressive to family) |
| I7, c.1081 + 1G > C | IVS6 Intron 7 | Splice | M | 3.8 | + | Normal | + | +/+ | not yet | not yet | not yet | Unclear speech | Good social interaction, very happy personality |
| E10, c.1612C > T | p.Gln538Ter | Nonsense | F | 4.5 | + | Strabismus | + | +/+ | 23 | NA | 2.5–3 years | First words at 3.4 years | Autism |
| 333 kb incl. entire gene and ex. 35–37 of ULK4 | Gross del | None | F | 5.2 | + | Hyperopia | + | +/- | 14 | NA | 4.5 years (ataxic) | At 4.5 years could combine several words, count to 10 | Friendly, social, short focus |
| 505 kb incl. entire gene | Gross del | None | M | 3 | + | Esotropia | + | +/- | NA | not yet | not yet | Babbles and say “mama” and “dada”, before age 3 years | Happy, good eye contact |
| MILD PHENOTYPE | |||||||||||||
| E13, c.1981C > T | p.Arg661Ter | Nonsense | F | 9.2 | + | NA | + | +/- | 11 | NA | 2.5 | First words at 3,4 years | Obsessional behavior; dyspraxia |
| E13, c.2038_2041dup | p.Ser681* | Nonsense | F | 13.2 | + | Strabismus, myopia | - | +/+ | 12 | NA | 1.5 | Mild, full sentences, but delayed | Social, autism, aggressive behavior, ADHD |
| E13, c.2038_2041dup | p.Ser681* | Nonsense | F | 11 | + | Strabismus, myopia | + | +/+ | 12 | 17 | 2 | Mild, full sentences, but delayed | Communicative, social, aggression, ADHD |
| NORMAL PHENOTYPE | |||||||||||||
| E14, c.2128C > T | p.Arg710Cys | Missense | M | NA | normal | FEVR | NA | Normal | Normal | normal | normal | normal | Normal |
| E15, c.2142_2157dup16 | p.His720* | Nonsense | M | NA | normal | FEVR | NA | Normal | Normal | normal | normal | normal | Normal |