Table 3.
Clinical table
| Family 1 | Family 2 | Family 3 | Family 4 | |||||
|---|---|---|---|---|---|---|---|---|
| Individual identifier | F.1-1 | F.1-4 (fetus) | F.1-6 | F.2-1 (fetus) | F.2-2 | F.3-1 | F.3-2 | F.4-3 |
| Gender (M/F) | F | F | M | F | M | F | F | M |
| Age at last examination, age at death or fetal age | 7 months, died at 25 months | 24 GW | birth, died at 4 months | 31 GW | 2 days, died at 22 days | 4 years 6 months | 11 months | 12 months, died at 16 months |
| Genetic data | ||||||||
| Ethnic origin | Tunisia | Algeria | Pakistan | Arab | ||||
| Consanguinity (yes/no) | yes | yes | no (parents unsure) | yes | ||||
| gDNA (GRCh38/hg38) | chr6(GRCh38): g.99613474del | chr6(GRCh38): g.99613479del | chr6(GRCh38): g.99614491A>T | chr6(GRCh38): g.99613435del | ||||
| cDNA (GenBank: NM_021620.3) | c.839del | c.844del | c.1856A>T | c.800del | ||||
| Protein | p.Ala280Glyfs∗21 | p.Val282Serfs∗19 | p.His619Leu | p.Gly267Aspfs∗34 | ||||
| CADD-PHRED score | N/A | N/A | 32 | NA | ||||
| Prenatal findings | ||||||||
| Prenatal growth retardation | − | − | − | − | − | + | + | − |
| Cerebellar vermis hypoplasia | + | + | + | + | + | not reported | not reported | not reported |
| Growth | ||||||||
| Delivery (weeks) | 39 | 24 | 37 | N/A | 34 | 39 | 37 | 40 |
| Neonatal symptoms | profound hypotonia | N/A | profound hypotonia | N/A | respiratory distress, axial hypotonia | temperature, HR and BP fluctuations; seizures | temperature, HR and BP fluctuations | respiratory distress, recurrent apnea |
| Likely autonomic symptoms | swallowing defect, desaturation, respiratory distress, bradypnea | N/A | swallowing defect, respiratory distress, no cough reflex, bradycardia | N/A | swallowing defect, respiratory distress, recurrent apnea, bradycardia | temperature, HR and BP fluctuations, respiratory distress | temperature, HR and BP fluctuations | respiratory distress, recurrent apnea |
| Weight at last examination (kg) | 7 (−0.8 SD) | N/A | N/K | N/A | N/K | 12.2 at 4 years 6 months (<−2 SD) | 5.0 at 7.7 months (−3 SD) | 5.2 (−4.5 SD) |
| HC at birth (cm) | N/A | N/A | N/K | N/A | 33.5 (+1.3 SD) | N/K | N/K | 34 (−1 SD) |
| HC at last examination (cm) | 42 (−0.9 SD) | N/A | N/K | N/A | N/K | 46.4 at 4 years 6 months (−2.7 SD) | 38.3 at 33 weeks 5 days (−4.7 SD) | 38 (−7 SD) |
| Presence of dysphagia | +, nasogastric tube feeding | N/A | +, nasogastric tube feeding | N/A | +, nasogastric tube feeding | − | − | +, nasogastric tube feeding |
| Developmental history | ||||||||
| Motor (normal/delayed/absent) | absent | N/A | absent | N/A | absent | delayed | delayed | absent |
| Global developmental delay (severity) | severe/profound | N/A | N/A | N/A | N/A | severe | mild | severe |
| Neurological features | ||||||||
| Axial hypotonia | + | N/A | + | N/A | + | + | + | + |
| Distal hypertonia | + | N/A | + | N/A | + | + | + | + |
| Spastic tetraplegia | + | N/A | N/K | N/A | N/K | − | − | + |
| Deep tendon reflexes | normal | N/A | N/K | N/A | N/K | reduced | normal | reduced |
| Epilepsy | ||||||||
| Seizure | − | N/A | − | N/A | − | neonatal period, focal seizures (on levetiracetam) | one seizure, on levetiracetam since | neonatal |
| Brain MRI | ||||||||
| Normal supratentorial brain | + | + | + | + | + | + | + | + |
| Cerebellar hemisphere hypoplasia | + | − | − | + | + | + | + | + |
| Cerebellar vermis hypoplasia | + | + | + | + | + | + | − | + |
| Brainstem hypoplasia | + | + | + | + | − | + | − | + |
| Associated clinical features | ||||||||
| Ophthalmological findings | abnormal ocular movement, suspicion of papillary edema or hypoplasia | N/A | bilateral retinal hemorrhages | N/A | no eye tracking | nystagmus with horizontal gaze, short sighted | − | − |
| Facial dysmorphism | microretrognathia | − | − | − | hypertelorism, epicanthic fold | − | − | hypertrichosis, low anterior hairline, upslanting palpebral fissures, epicanthic folds |
| Oral cavity findings | posterior cleft palate | posterior cleft palate | − | − | − | − | − | − |
| Cardiac abnormalities | − | trabecular ventricular septal defect | ostium secundum atrial septal defect, patent ductus arteriosus | − | N/A | sinus rhythm with occasional marked sinus arrhythmia | − | − |
| Gastrointestinal abnormalities | − | − | gastroesophageal reflux | − | − | − | − | recurrent vomiting, gastroesophageal reflux |
| Respiratory system | oxygen therapy required (nasal canula) | − | oxygen therapy, base of the tongue ptosis, no cough reflex | − | apnea, oxygen therapy required in the context of prematurity | respiratory distress | − | poor respiratory effort, ventilation dependence |
| Other | N/A | mild extremity malpositions | mild feet malpositions | N/A | N/A | postural kyphosis | episodic dystonia | N/A |
Abbreviations: BP, blood pressure; EEG, electroencephalography; HC, head circumference; HR, heart rate; N/A, not applicable; N/K, not known; SD, standard deviation.