Table 1.
Review of systems in our cohort of six patients
| Individual 1 | Individual 2 | Individual 3 | Individual 4 | Individual 5 | Individual 6 | |
|---|---|---|---|---|---|---|
| Variant (Hg19; NM_016148.5) | 19-51171728-C-CG | 19-51171862-C-A | 19-51171902-GC-G | 19-51207401-G-A | 19-51170717-GGGCT-G | 19-51217196-CA-C |
| c.3488dup | c.3355G>T | c.3314del | c.1198C>T | c.4496_4499del | c.650del | |
| p.Ser1164ValfsTer4 | p.Glu1119* | p.Gly1105AlafsTer238 | p.Arg400* | p.Gln1499fs | p.Leu217* | |
| Inheritance | De novo | De novo | De novo | De novo | De novo | De novo |
| ACMG/AMP Classificationa | Pathogenic | Pathogenic | Pathogenic | Pathogenic | Pathogenic | Pathogenic |
| Gender | Male | Female | Male | Male | Male | Female |
| Age at last examination | 11y | 6y | 7y | 9y | 10y9m | 11y3m |
| Height at last examination | 143cm (−0.07 SD) | 109cm (+1.60 SD) | 115cm (+1.34 SD) | 134.5cm (+0.16 SD) | 144.5cm (+0.88 SD) | 136cm (−19.98 SD) |
| Weight at last examination | 36kg (+0.01 SD) | 18.1kg (+0.76 SD) | 21.5kg (+0.99 SD) | 28.7kg (+0.02 SD) | unknown | 24kg (−2.36 SD) |
| Head circumference at last examination | unknown | 50cm (−0.32 SD) | 50.5cm (−0.36 SD) | 55.5cm (+2.17 SD) | 58.5cm (+3.97 SD) | 49.8cm (−2.29 SD) |
| Ethnicity | Italian | Egyptian | European, Mexican, Pakistani | European | European | Brazilian |
| Motor development/ delays | Walked at 16mo, overall mild gross motor delay | Walked at 18–19mo | Walked at 16mo | Walked at 2yo, mild motor delay | Walked at 20mo, poor balance | Never walked |
| Speech & language development/ delays | First words at 2yo, still concerns with speech at 3yo; significant expressive language deficits and articulation disorder, low facial tone, compromised oral motor skills | First words at 2yo; speech delay, mixed receptive expressive language disorder | First words at 12mo; mixed receptive expressive language disorder | First words at 2yo; low facial tone; gross language delay | Babbled at about 10mo, then no further words until about 5yo; at 10yo only says occasional single words, understands simple commands | At 11y3mo nonverbal |
| Cognitive delays/ID/ learning disabilities | Auditory processing disorder, difficulty with executive functioning, mathematic concepts, verbal reasoning and problem solving | Intellectual disability | Intellectual disability | Severe learning difficulties | Intellectual disability | Severe intellectual disability |
| ASD | No | Yes | No | Yes | Yes | No |
| Other neuropsychiatric and behavioral issues | Anxiety, ADHD | Hyperactivity and hair pulling when upset | No | Anxiety | Anxiety, tic (head jerk), anger outbursts, self-biting | Puts hands inside the mouth, but won’t bite hard |
| Seizures (seizure type, age of seizure onset) | No | No, abnormal EEG consistent with a seizure disorder of multifocal origin; has not had a clinical seizure | Yes, one generalized tonic-clonic seizure, one seizure consisting of general convulsions lasting 3–4 minutes, both onset at 7yo; abnormal EEG | No | No | Yes, myoclonic seizures onset at 11mo; evolved into focal to bilateral tonic-clonic seizures at 14mo; abnormal EEG |
| Hypotonia | Yes (as a newborn) | Yes (mild) | Yes (mild) | No | Yes (mild) | No |
| Headaches/migraines | Yes | No | No | No | No | No |
| Macrocephaly (≥ 2SD) | No | No | No | Yes (+2.17 SD) | Yes (+3.97 SD) | No |
| Microcephaly (≤ 2SD) | No | No | No | No | No | Yes (−2.29 SD) |
| Brain imaging abnormalities | N/A | Normal MRI | Normal MRI | N/A | N/A | Abnormal MRI: absent cerebellar vermis, possible dysgenesis with partial fusion of the cerebral hemispheres and thalami |
| Dysmorphic features | No | Prominent forehead, midface hypoplasia | Clinodactyly, left epicanthal fold | Dolichocephaly, high implantation of the hair with bilateral frontal upsweep, posteriorly rotated ears, short philtrum, thick lower lip, diastema, tapering fingers, long toes | Pronounced cupid’s bow, pes planus, soft skin | No |
| Other | Feeding difficulties | Exotropia, constipation | Unilateral clubfoot | Joint laxity; soft, doughy skin, GERD | Partial holoprocencephaly |
SI conversion factors: To convert height and head circumference to inches, divide values by 2.54. To convert weight to pounds, divide values by .45.
ACMG/AMP: American College of Medical Genetics and Genomics and Association of Molecular Pathology, ASD: autism spectrum disorder, ADHD: attention deficit hyperactivity disorder, EEG: electroencephalogram, GERD: gastroesophageal reflux disease, MRI: magnetic resonance image, N/A: not assessed.
a
ACMG/AMP classification according to the guidelines of Richards et al43.