Table 1.
Molecular and phenotypic summary of 16 probands with de novo variants in CNOT3
| Case | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Variant | c.58G > C | c.142C > G | c.355A > G | c.439G > A | c.562C > T | c.563G > A | c.563G > A | c.2090G > A | c.732dup | c.821_825dup | c.1127_1145del | c.1473_1474del | c.1538_1541del | c.1866G > A | c.1926_1927del | c.2080C > T |
| Effect | p.(Glu20Gln) | p.(Leu48Val) | p.(Lys119Glu) | p.(Glu147Lys) | p.(Arg188Cys) | p.(Arg188His) | p.(Arg188His) | p.(Arg697Gln) | p.(Ser245Glnfs*8) | p.(Asn276Glnfs*61) | p.(Ala376Glyfs*61) | p(Gly493Thrfs*21) | p.(Ser513Metfs*27) | p.(Trp622Ter) | p.(Cys643Serfs*39) | p.Gln694Ter |
| Type of variant | Missense | Missense | Missense | Missense | Missense | Missense | Missense | Missense | Truncating | Truncating | Truncating | Truncating | Truncating | Truncating | Truncating | Truncating |
| Open access DECIPHER ID | 261122 | 276825 | 262450 | 259521 | 268198 | 263217 | 327692 | 357220 | 257816 | |||||||
| Age at diagnosis (years) | 8 | 5 | 17 | 12 | 12 | 21 | 6 | 8 | 12 | 15 | 18 | 18 | 7 | 55 | 4 | 19 |
| Gender | F | M | M | M | M | F | F | F | M | M | F | M | M | M | M | F |
| Ethnicity | Caucasian | White British | Dutch Caucasian | French Caucasian | ? | White British | White British | White British | Caucasian | Dutch | French Caucasian | Caucasian | French Caucasian | Dutch Caucasian | Caucasian | Caucasian |
| Birth weight | 3487 g | 2211 g | 2970 g | 1900g | 2100 g | 2400 g | ? | 3005 g | 3856 g | 3120 g | 2820 g | 2000g | 2870 g | 3500 g | 3220 g | 2870 g |
| Gestation (weeks) | 40 + 6 days | 39 | 39 | 32 | 38 | 40 | 40 + 6 days | 37 | 38 | 40 | 37 | 36 | 37 + 2 days | 40 | 40 | 38 |
| Peri/postnatal issues | Hip dysplasia requiring harness | Fetal tachycardia, cord round neck | CS (breech) | CS | Remained in hospital for 1 week requiring incubation, oxgyen and antibiotics | Brachycephaly, floppy, readmitted day 10 with seizures | Induced because of pre-eclampsia, cyanotic episode 2 h after birth | Oblique lie, elective CS | None | None | None | None | Feeding difficulties | None | None | None |
| Walked independently (age - in months) | 27 | 35 | 36 | 30 | ? | 22 | 21 | 26 | Cruising furniture at 30 months | 15 | 17 | 24 | 35 | 24 | 55 | 14 |
| Motor development | Fine motor skills remain delayed | ? | Mild–moderate fine and gross motor delay | Fine and gross motor delay | Able to walk but uses wheelchair for longer distances | ? | Delay in gross and fine motor skills | Fine and gross motor delay | Comparatively good fine motor skills | Fine motor development normal, some delay of gross motor skills but now able to cycle | Delayed fine motor skills, can run with difficulty and slowly climb stairs | Fine and gross motor delay | Fine and gross motor delay | Fine and gross motor delay, able to cycle at 10 years old | Fine and gross motor delay | ? |
| Abnormailty of tone | Hypotonia (resolved) | Hypotonia | Hypotonia | No | No | Early hypotonia | Hypotonia | Hypotonia | Borderline hypotonia | ? | Hypotonia | ? | Hypotonia | ? | Hypotonia | ? |
| Speech and language development | 50 makaton signs only at 3 years; some speech, good understanding at 6.5 years | First words after 2 years; at 4 years mainly repeats words | Nasal speech | No language | No words | No words | 3 single words by 21 months, now talks in sentences although words can be indistinct | Delayed | No expressive language skills, hoarse voice | Delayed, nasal speech | First words aged 17 months, diffculty in communicating with others but does form some complete sentences | Delayed, talks in full sentences now | Delayed | First words aged 3 years, has developed speech, verbal dyspraxia | No language | Speech from 5 to 6 years, now short phrases and echolalia |
| Head circumference centile | 5.5 cm < 0.4th centile | 75 | 25–50 | 25–50 | 75 | 75–91 | 50–75 | 1.5 cm < 0.4th | 75–91 | 25–50 | 9–25 | 25–50 | 25–50 | 25 | 50 | 50–75 |
| Height centile | 25 | 0.4–2 | 25 | 0.4–2 | 2–9 | 0.4–2 | 9–25 | 50 | 2 | 9–25 | 50–75 | 9 | 9–25 | (Adult height 173 cm) | 0.4–2 | 0.4–2 |
| Weight centile | 2–9 | 9–25 | 25–50 | 0.4 | 75 | 2–9 | 25–50 | 25 | 0.4–2 | 9–25 | 91 | 75–91 | 50 | (Adult weight 72 kg) | 0.4–2 | ? |
| Learning and behaviour | 1:1 full time help in mainstream school | Moderate LD; attends mainstream school and special needs nursery aged 4; reduced eye contact and sensory processing disorder | IQ 52, hand flapping, pervasive developmental disorder not otherwise specified | Severe LD, autism, behavioural steriotypies | Severe autism | Profound LD | Requires extra support at mainstream school | Attends mainstream school with additional support | Marked autism | Autistic spectrum disorder, learning difficulty | Anxiety, aggression, unable to read or write, special needs school | Autism, attends special needs school | Autism | Unable to read or write, learning level of a 6 year old, works in a social empoyment facility | Autistic spectrum disorder, learning diffculty | Severe LD, sensory issues and rocking movements |
| Hearing and vision | Glue ear | Conductive hearing loss | Hypermetropia (+5 dioptres) | Nystagmus | Strabismus | Normal | Moderate− severe left-sided SNHL; right conductive hearing loss; intermittent right strabismus | ? | Normal | Strabismus | Esotropia | ? | Normal | Strabismus, optic nerve atrophy | Normal | Strabismus, visual processing disorder, bilateral discrete raised lesions superior to optic discs?calcium deposits secondary to retinal haemorrhage |
| Dysmorphic features | Large central incisors, downturned mouth, flat broad nose, 2 right ear pits | Prominent forehead, mild cranial asymmetry, hypotelorism, deep-set eyes, right helix squared off and dimple on lobe, short nose with depressed bridge, upturned nares | Prominent occiput and foreheed, low set ears, prominent nasal tip, mild prognathism, short philtrum, tapering fingers, bilateral 5th finger clinodactyly, flat feet | Malar hypoplasia, prognathism, doliocephaly | Brachycephaly, flat midface, hypertelorism, upslanting palpebral fissures, two crowns over posterior parietal area with midline join of the hairgrowth, tapering fingers | Prominent forehead, deep set eyes, small hands and feet | Left plagiocephaly, low post hairline, upper back and arms hirsute, prominent lower jaw | Plagiocephaly and brachycephaly, small ears with short upturned lobes, short philtrum, dimples over shoulders, bilateral talipes calcaneo-valgus | Prominent forehead, flat nasal bridge, macroglossia, short tapering fingers, small feet | Small triangular skull, coarse hair, narrow nasal bridge, long columella, short philtrum, prominent eyebrows | Slightly descending columella, tubular nose, narrow palate, misaligned teeth, upslanting palpebral fissures, malar hypoplasia, 5th finger clinodactyly, short hands | Low frontal hairline, simple helices with fleshy earlobes | Small chin, malar hypoplasia, dolicocephaly | Deep set eyes, slight hypotelorism | Prominent forehead | Straight, heavy eyebrows, deep set eyes, upslanting palpebral fissures, short philtrum, full lower lip, full slightly overhanging nasal tip, long fingers |
| MRI brain | Myelination delayed at 2 years, resolved by 3 years; slim corpus callosum | Aged 11 months mild prominence of ventricular system with normal brain parenchyma | Normal 3.5 years | Thin corpus callosum (4 years) | Small hippocampus and amygdala aged 3 | Global cerebral and cerebellar atrophy aged 18 years, with mega cisterna magna and thickened corpus callosum | Not done | Not done (did have normal CT brain) | Normal aged 2 years | Normal aged 6 years | Occipital atrophy 3.5 years | ? | Normal | Normal | Possible partial agenesis of the corpus callosum | Not done |
| Heart and kidneys | Normal echo and renal USS | Small left kidney (VUR) | ? | Pyelocalyceal hypotonia | Perimembranous VSD | ? | Normal renal USS | Normal renal USS | Trivial aortic regurgitation aged 5 years; normal renal USS | Normal echo aged 5 years | Normal echo | ? | Normal renal USS; abnormal right pulmonary venous return | ? | Normal echo and renal USS aged 3 years | ? |
| Other features | Some excess hair over cheek bones, marked microcephaly | Elbow dimples, deep plantar creases, right lower leg capillary naevus, reduced pain sensation | Scoliosis, persistent primary dentition (at 12 years), frequent infections, seizures from 4 years | Paroxysmal staring events with focal abnormalities on EEG, delayed bone age, wormian bones, delayed dentition, hypermobility, persistent fontanelle | Seizures started 10 weeks of age, frontal lobe epilepsy from around age 3; stable thoracolumbar scoliosis | Borderline biotinase level (replacement started december 2015), high-pitched scream as an infant, torticollis noted at 6 weeks | Tongue tie, blind ending sacral dimple | Delayed bone age, lower thoracic kyphosis, possible small genitalia | Pes planovalgus | Varus foot deformity | Soft skin, hypermobile joints, penile hypopigmentation, inguinal hyperpigmentation, temporal lobe epilepsy diagnosed aged 13 years, melatonin for sleep | Tremor left hand, prone to respiratory tract infections, high cholesterol, late puberty | Positional plagiocephaly | Scoliosis, hairy, episodes of hyperventilation |
RefSeq NM_014516.3