Table 1.
Clinical Features of the Subjects with Frameshift Variants in NOVA2
| Individual | Ind 1 | Ind 2 | Ind 3 | Ind 4 | Ind 5 | Ind 6 |
|---|---|---|---|---|---|---|
| Variant in NOVA2 (NM_002516.3) | c.782del (p.Val261Glyfs∗135) | c.710_711dup (p.Leu238Cysfs∗159) | c.701_720dup (p.Ala241Profs∗162)a | c.709_748del (p.Val237Profs∗146) | c.781del (p.Val261Trpfs∗135) | c.720_721insCCGCGGATGTGC TTCCAGCC (p.Ala241Profs∗162)a |
| Occurence | de novo | de novo | de novo | de novo | not present in the mother | de novo |
| Sex | male | male | female | female | male | female |
| Age at assessment | 5 y 6 m | 2 y 1 m | 2 y 2 m | 2 y 7 m | 21 y | 5 y 5 m |
| Clinical Examination | ||||||
| Birth weight (grams) | 3,515 | 3,640 | 2,327 | 3,459 | N/A | 3,750 |
| Birth length (cm) | 50 | 51 | N/A | 48 | N/A | 51 |
| OFC at birth (cm) | 35 | 36 | N/A | N/A | N/A | 34 |
| Weight (kg/SD) | 14/−2.5 SD | 9.6/−2 SD | 10.38/−1.8 SD | 10.5/−2 SD | N/A | 16/−1 SD |
| Length (cm/SD) | 100/−2 SD | 81/−2 SD | 82.8/−1.5 SD. | 85/−2 SD | N/A | 108/0 SD |
| OFC (cm/SD) | 49/−0.5 SD | 46/−1 SD | 45/−1.8 SD | 46.8/−1 SD | N/A | 48/−2 SD |
| Facial dysmorphy | see Figure 1 | see Figure 1 | N/A | high hairline, brachycephaly, downslanting palpebral fissure, downturned mouth, bilateral ptosis | no | deeply set eyes, anteverted nares, deeply grooved philtrum, see Figure 1 |
| Congenital malformations | none | none | none | limb malformation | none | none |
| Neurological Manifestations | ||||||
| Intellectual disability | + | + | + | + | + | + |
| Motor developmental delay | + | + | + | + | + | + |
| Speech delay | + (no word) | + | + (no word) | + (no word) | + (no word) | + |
| Behavioral disorders | + (autistic traits) | + (anger, autism) | − | + (hypersensitivity when people touch her head and hair) | + (autism) | − |
| Stereotypic movements | + | + (hands) | − | + (hands) | + | + (hand flapping) |
| Hypotonia | N/A | N/A | + | + | − | + |
| Seizures | + | − | − | − | + | − |
| Spasticity/Ataxic gait | + | + | + | − | − | + |
| Frequent laughter | + | − | − | + | − | − |
| Attraction with water | + | − | − | − | − | − |
| Feeding difficulties | + | + | − | + | + | + |
| Magnetic resonance imaging of the brain | cortical atrophy | normal | Chiari malformation, type 1 | corpus callosum thinning and incidental pineal gland cyst | corpus callosum thinning, global white matter volume loss, slight cerebellar volume loss | normal |
| Previous Genetic Testings | ||||||
| Angelman-related genetic investigations | + | + | − | + | − | + |
| Other previous genetic investigations | N/A | X fra, CGH-array, ARX, CDG | SNP array | SNP array, MECP2 sequencing | SNP array | SNP array, MECP2, FMR1, FOXG1, metabolic screening, gene panel of intellectual disability: VUS in CDKL5 |
Abbreviations: +, present; –, absent; N/A, not available; OFC, occipital frontal circumference; SD, standard deviation. hg19 coordinates.
a
Consequences of variants identified in individuals 3 and 6 differ from only one amino acid (a cysteine residue for individual 3 and a phenylalanine one for individual 6 at amino acid position 245)