Table 1. Overview patient information.
| Patient | 1 | 2 | 3 | 4 | 5 (Son of 6) | 6 (Father of 5) | 7 | 8 | 9 | 10 |
|---|---|---|---|---|---|---|---|---|---|---|
| Method | Exome trio | Exome trio | Panel NGS | Panel NGS | Exome trio | Genome trio | Panel NGS | Exome trio | Exome trio | Exome trio |
| Age at last examination | 13 years | 7.5 years | 20 years | 30 months | 21 years | 45 years | 16 years | 4 years | 10 years | 3 years |
| Sex | F | F | F | F | M | M | F | F | F | F |
| OFC (SD) | 0 | −2.5 | −2 | −2.5 | M | M | −1 | −1.8 | +1 | +1.5 |
| Height (SD) | 0 | na | −3 | −2.5 | +0.5 | +0.5 | −1.8 | 96.5 cm | na | 0 |
| Weight (SD) | +0.5 | na | na | −2.5 | <+5 | 0 | na | 16 kg | −0.5 | +1.8 |
| Pregnancy or delivery event | No | Placenta accreta | No | Club foot | Mild pre-eclampsia | Reduced fetal movements | No | C-section Breech position |
Pre-eclampsia C-section | No |
| Maternal treatment | No | No | No | No | Enoxaparin injections | Codeine –tooth abscess | Antiretroviral therapy | No | No | Heparine therapy |
| Birth (weeks) | 40 | Full term | 41 | 40 | Full term | 42 | na | 39 | 37 | 40 |
| Birth OFC (cm) | 33.5 | na | 36 | 34.5 | na | na | 34 | 35.6 | na | na |
| Birth weight (g) | 3020 | 3500 | 3140 | 3150 | 3090 | 3360 | 3080 | 3570 | 2637 | 3430 |
| Birth length (cm) | 44 | na | 48 | 47 | na | na | 47.5 | 50.8 | na | 50 |
| First signs (age) | Unstable gait (14 months) | Poor visual contact (1 month) | Hypotonia and poor visual contact (first weeks) | Lack of visual pursuit (3 months) | Motor delay (first months) | Mild learning difficulties | Poor visual contact (first weeks) and abnormal ocular movements | Feeding difficulties hypotonia and no visual tracking (3 months) | Neonatal hypotonia and abnormal ocular movements | Motor delay (first months) |
| Hypotonia first months | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No |
| Achieved psychomotor milestones | Able to walk unaided (ataxic) | Able to walk with aid | Able to sit, hypotonia, moves on the buttocks, and poor visual contact | Unstable head, hypotonia, and unable to follow | Able to walk unaided after motor delay | Able to sit unaided with delay | Able to walk unaided after motor delay | Unable to walk | Unable to walk | Able to sit: 12 months |
| Walking age | 25 m (ataxic) | 4 years with aid | Not acquired | Not acquired | 19 months | Normal | 20 months | Not acquired | Not acquired | 24 months |
| Ataxia | Yes | Yes | Severe hypotonia | na | No | No | Yes, improving; at 16: very mild | na (unable to walk) | No | Yes |
| Tremor | Yes | No | No | No | No | No | Yes (hands) | No | No | No |
| Dysmetria | Yes | na | na | na | No | No | Very mild and adiadococinesia | Yes | No | na |
| Dysarthria | Yes | na | na | na | No | No | na | Non-verbal | No | na |
| Dystonia | No | na | Yes | No | No | No | hand ‘crispation’ | No | na | No |
| Abnormal movements | Myoclonies | na | Saccadic gesticulation | No | No | No | Syncinesia | Stereotyped hand movement | na | Ataxia |
| Amyotrophy | Yes | na | na | na | na | na | na | na | na | No |
| Epilepsy (age and treatment) | No | Febrile seizures (5 years, no treatment) | No | Doubtful seizures and abundant interictal discharges (4 years, primidone) | Nocturnal epilepsy generalized tonic-clonic (7 years, no treatment) | No | No | Doubtful | Neonatal episodes (uncertain) | Yes (30 m, primidone) |
| EEG: age/findings/(Wake W/Sleep S) | na | 5 years: Background slowing (W); episodes of sharp waves in the fronto-central regions (S) | 1/8 years: Normal (W/S) | 30 months: Normal EEG 4 years: Background slowing, alpha central since 6 m, biparietal spikes, no epilepticus during slow-wave sleep (ESES; W/S) | 7 years: bifrontal synchronous spike and waves discharges (W) | na | na | 3 years: Generalized -background slowing, no eptileptic dicharges (W/S) | Several before 10 years: Normal (W/S) | 2.5 years: ESES (W/S) |
| Pain insensitivity (Y/N)? | No | Yes | na | na | Yes | Yes | na | na | No | Yes |
| Heat insensitivity | No | No | na | na | No | Yes | na | Yes | No | na |
| Language | Normal | Monosyllabic | Absent | Absent | Delayed | Normal | Slightly delayed then normal | Non-verbal (picture cards) |
Non-verbal (picture cards) | Delayed |
| Intellectual deficiency | Normal low/mild ID | Severe–moderate | Severe | Probably severe | Moderate | Mild | Very mild-low normal | Moderate | Severe | Yes |
| Behavior anomalies | No | No | No | No | Food-seeking | No | No | Yes | Occasional outbursts and stereotypies ‡ | Aggressivity |
| Autism spectrum disorder (Y/N)? | No | No | Poor contact (severe ID) | Poor contact (severe ID) | No | No | No | No | Yes | Yes |
| School | Special school (attention deficit and slow) | Specialized institution | Institution for children with profound intellectual and multiple disabilities | na | Special education | Normal then special education | Mainstream school with support measures, able to read, writing difficulties, and slow | Foundation for Blind School making slow progress | na | na |
| Evolution | Progress | Progress | Stable | Stable | Progress | Progress | Progress | Progress but episodes of mild psychomotor regression concomitant with behavioral fluctuations | na | Progress |
| Ocular anomalies |
Strabismus, saccadic breakdown of smooth pursuit |
Abnormal eye pursuit | Strabismus | No | Hypermetropia and left convergent squint | No | Nystagmus | Cortical visual impairment, nystagmus, and strabismus | Disconjugate nystagmus | Strabismus |
| Skeletal anomalies |
12th hypoplastic rib pair | Pes calcaneovalgus | Congenital hip luxation – later paralytic kyphoscoliosis | na | Left Perthes’ disease | No | Valgus foot and patellar dislocation | No | Hip dysplasia | Brachydactyly |
| Others | Small genitalia, delayed puberty, and gynecomastia | Skin tags and dry palmar skin | Prognathism | Failure to thrive (milk protein allergy and GERD) | Feedings difficulties G-tube fed | Immune thrombocytopenia and hypochromic microcytic anemia | ||||
| MRI (age) | 3 years 8 months: cerebellar atrophy, increased at 10 years | 6 months: normal 2 years 2 months: cerebellar vermis and hemispheres atrophy | 4 months: ‘normal’ 8 months: brainstem and cerebellar atrophy, short corpus callosum | 1 years 4 months: brainstem and cerebellar atrophy | Normal | Not done† | Very mild localized atrophy of cerebellar hemispheres | Normal | Not done* | Normal (3 years) |
| Mutation NM_001366145.2 | c.1841A>T p.(Asp614Val) | c.2305C>G p.(Leu769Val) | c.3004G>T p.(Val1002Leu) | c.3005T>G p.(Val1002Gly) | c.3019G>A p.(Gly1007Ser) | c.3019G>A p.(Gly1007Ser) | c.3019G>A p.(Gly1007Ser) | c.3376A>G p.(Asn1126Asp) | c.3376A>G p.(Asn1126Asp) | c.3397T>C p.(Ser1133Pro) |
| Inheritance | de novo | de novo | de novo | de novo | Inherited from the father | de novo | de novo | de novo | de novo | de novo |
Abbreviations: NGS = Next Generation Sequencing; OFC = occipitofrontal circumference.
*
Cerebral computed tomography (CT) at 5 years: Periventricular white matter loss.
†
CT normal.
‡
repetitive hyperventilation.