Table 1.
Clinical Findings in Five Subjects with De Novo Missense Variants in CHD4
| Subject 1 | Subject 2 | Subject 3 | Subject 4 | Subject 5 | |
|---|---|---|---|---|---|
| CHD4 variant | c.3380G>A (p.Arg1127Gln) | c.3518G>T (p.Arg1173Leu) | c.3380G>A (p.Arg1127Gln) | c.3443G>T (p.Trp1148Leu) | c.3008G>A (p.Gly1003Asp) |
| Gender, age at last exam | male, 10 years | female, 16 years | male, 10 years | female, 5 years | male, 18 years |
| Birth weight, OFC | 4 kg, 38 cm | 2.8 kg, ND | 3.7 kg, 37cm | 2.99 kg, 35 cm | 3.06 kg, ND |
| Height, OFC at last exama | 143 cm (75th), 56 cm (>98th) | 161 cm (40th), 62 cm (>98th) | 140 cmb (50th), 56 cm (>98th) | 89.5 cm (<3rd; Z score −5), 49 cm (20th) | 167.5 cm (10th), 52.5 cm at 4 years (90th) |
| Developmental delay | + | + | + | + (severe) | + |
| Intellectual disability | + | + | + (mild) | + | + (mild) |
| Hearing lossc | + | + | + | − | + |
| Undescended testis, micropenis | +, + | NA | +, + | NA | −, + |
| Macrocephalyd | + | + | + | relative to length | +e |
| Widely spaced eyesf | + | + | + | + | + |
| Dysmorphic earsg | + | + | + | + | + |
| Palatal anomalies | +h | − | +i | +i | +i |
| Hypogonadotropic hypogonadism | + | − | + | NT | + |
| Skeletal survey | advanced bone age by 2–3 years | tarsal coalition, cervical vertebrae fusion | falx calcification | scoliosis, platybasia, fusion of C2-C3, bilateral coxa valga, fusion of the cuboid and the 3rd cuneiforms bilaterally, brachymesophalangia | diffusely osteopenic bones |
| Brain MRI | enlarged lateral ventricles, congenital stroke with moyamoya disease | enlarged lateral ventricles, chiari 1 malformation | enlarged lateral ventricles | enlarged ventricles (mild), basilar, invagination and narrow foramen mangum | enlarged lateral and third ventricles |
| Heart | – | – | – | congenital heart defect (PDA s/p ligation, PFO, ASD, and VSD) | ASD, PDA s/p repair, VSD, bicuspid aortic valve, mild dilatation of aortic root |
Abbreviations are as follows: ASD, atrial septal defect; NT, not tested; NA, not applicable; OFC, occipital frontal circumference; PDA, patent ductus arteriosus; VSD, ventricular septal defect.
a
Data in parentheses are percentiles.
b
On growth hormone therapy.
c
Conductive and/or sensorineural hearing loss.
d
Head circumference >97th percentile for age and sex.
e
Current OFC unavailable, 90th percentile at the age of 4 years.
f
Inner canthal distance >97th for age 50.
g
See a description of ear anomalies in Figure 1.
h
Bifid uvula.
i
Hypernasal speech and or velopharyngeal insufficiency/submucosal cleft palate.