Table 1.
Comparison of Clinical Features of Affected Individuals with the p.Arg913Ter or p.Arg1163Trp ZSWIM6 Variants
| ZSWIM6 Variant/Affected Individual | p.Arg913Ter Affected Individual 1 | p.Arg913Ter Affected Individual 2 | p.Arg913Ter Affected Individual 3 | p.Arg913Ter Affected Individual 4 | p.Arg913Ter Affected Individual 5 | p.Arg913Ter Affected Individual 6 | p.Arg913Ter Affected Individual 7 | Summary p.Arg913Ter Cohort (n = 7) | Summary Postnatal Non-mosaicap.Arg1163Trp Cohort (n = 6) |
|---|---|---|---|---|---|---|---|---|---|
| Method of testing and confirmation | WGS of proband, SS to confirm and segregate in family | Trio WES, SS confirmation | WES of proband, SS to confirm and segregate in family | WES of proband, SS to confirm and segregate in family | WES of proband, SS to confirm and segregate in family | trio WGS, SS to confirm and segregate in family | trio WES, SS confirmation | – | – |
| Inheritance, if known; parental ages at birth of child | not maternal;b paternal 32, maternal 32 | DN; paternal 31, maternal 28 | DN; paternal 34,maternal 25 | DN | DN; paternal 33, maternal 32 | DN; paternal 32, maternal 31 | DN; paternal 30, maternal 29 | 6/7 DN; 1/7 unknown | 4/6 DN; 1 NT; 1/6 inherited from mosaic parent |
| Evidence of mosaicism? (wild-type: mutant reads) | no (32:22) | no (75:62) | no (121/257) | no (99/191) | no (69/165) | no (50:50) | no (24:25) | – | – |
| Age (year) | 16 | 7 | 4 | 5 | 3 | 29 | 29 | 3–29 years | unknown |
| Gender | M | F | F | F | F | M | M | 3/7 male (43%) | 4/6 male (67%) |
| Level of ID | severe-profound | severe | severe | severe | severe | profound | severe | 7/7 severe-profound (100%) | 6/6 severe (100%) |
| OFC | normo-cephaly | progressive microcephaly (−2 SD) | progressive microcephaly | normocephaly | progressive microcephaly | progressive macro-cephaly to 90–97th centile | normo-cephaly | progressive microcephaly 3/7 (43%); progressive macrocephaly 1/7 (14%) | NR |
| Infantile hypotonia/delayed GM milestones? | + | + | + | + | + | + | + | 7/7 (100%) | 6/6 (100%) |
| ASD? | + | − | + | + | + | − | + | 5/7 (71%) | NR |
| Communication | non verbal | non verbal; limited comprehension | gestures; non verbal | few words; PECS | babble and one word (no); starting to use PECS | vocalizes, one sign | short sentences, articulation difficulties | 6/7 non-verbal or only few words (86%) | 2/2 non-verbal (100%) |
| Ambulation | non ambulant (wheelchair); previously ambulant at 2.5 yr with wide unsteady gait | ambulant (from 3 year) with wide-based ataxic gait | ambulant with wide unsteady gait (from 2 year) | ambulant with wide unsteady gait, stroller used for distances | starting to cruise | ambulant with wide-based gait; wheelchair for distances | ambulant with broad-based unsteady gait | 5/7 ambulant (71%) with wide-based gait | 2/2 non ambulant (100%) |
| Temperament/behavior | happy, affectionate, interested in family and TV; hyperactivity | happy; bursts of laughter; hyperactivity | happy; hyperactivity; repetitive behaviors; pica | interactive and sociable | no behavioral concerns | happy, affectionate; loves music and water play | happy; hyperactivity and attention deficit; history of pica | 4/7 hyperactivity (57%) | NR |
| Epilepsy | + (GTC and focal dyscognitive) | – | (under investigation for starting episodes and unusual movements) | – | + (IS: controlled with medication) | + (infrequent GTC and absence from age 9) | + possible absence seizures (no medication) | 4/7 seizure/possible seizure disorder (57%) | 1/6 (17%) |
| Progressive spasticity | + | − | − | + | − | + | − | 3/7 (43%) | NR |
| Movement disorder? | paroxysmal hypertonicity; unusual tongue movements | stereotypical hand movements; midline tongue protrusion; ataxia | paroxysmal hypertonicity; unusual tongue movements; ataxia | body rocking; ataxia | stereotypical hand movements; ataxia | − | ataxia, tongue thrusting, head tics | 6/7 (86%) | NR |
| Ophthalmological features | impairment lateral gaze | strabismus | − | accommodative esotropia | right sided esotropia | − | right sided esotropia | 5/7 (71%) | variable: cataract, glaucoma, myopia, optic nerve hypoplasia |
| Brain MRI | cortical atrophy (13 year) | normal | normal | normal (7 mo) | normal | mild cortical atrophy (22 mo) but later MRI considered normal | normal | cortical atrophy 1/7 (14%) | interhemispheric lipoma 6/6 (100%); abnormal corpus callosum 3/6 (50%); other abnormalities variable |
| Additional neurological features | mixed peripheral neuropathy | – | truncal hypotonia, abnormally high pain threshold | truncal hypotonia | bilateral ankle pronation and toe pointing, torticollis | full neurological examination not possible | abnormally high pain threshold, self-sustained injuries | 5/7 (71%) | NR |
| Gastro-intestinal symptoms | failure to thrive and severe GERD requiring fundoplication; constipation; ulcerative colitis from mid-teens | infantile cow’s milk protein intolerance; recurrent diarrhea and vomiting from 18 mo improved on gluten-free diet | GERD | severe GERD requiring gastrostomy | GERD and failure to thrive | – | intermittent constipation | 6/7 (86%) significant GI symptoms | NR |
| Additional non- neurological features | marked equinovarus deformity of feet; thoracolumbar scoliosis, distinctive facial features | distinctive facial features | otitis media with effusions (requiring tympanostomy); distinctive facial features | premature eruption of teeth; distinctive facial features | distinctive facial features | facial asymmetry; premature eruption of teeth; puberty at 12; male pattern baldness by age 17; distinctive facial features | severe bilateral planovalgus; nocturnal eneuresis; distinctive facial features | – | 5/6 (83%) limb abnormalities; 2/4 males (50%) cryptorchidism; 1/6 (17%) scoliosis; 2/6 (33%) hypopituitarism; 6/6 hyperteloric (100%); 4/6 median facial cleft 67%); 4/6 cleft palate (67%) |
Abbreviations: AFO, ankle foot orthoses; ASD, autism or autism spectrum disorder; DN, de novo; WES, whole-exome sequencing; GM, gross motor; GERD, gastro-esophageal reflux disease; WGS, whole-genome sequencing; GTC, generalized tonic-clonic; ID, intellectual disability; IS, infantile spasms; mo, months; MRI, magnetic resonance imaging; ND, not done; NR, not relevant; NT, not tested; OFC, occipital frontal circumference; PECS, picture exchange communication system; SS, Sanger sequencing; yr, year.
a
Mildly affected mother with mosaicism and fetus terminated at 20 weeks excluded.
b
Not inherited from mother, not present in either of two unaffected brothers, father not available for testing.