Main clinical features
- Intellectual disability: to date all affected individuals have a severe-to-profound ID and require early developmental interventions or special schooling. The two oldest individuals in our reported cohort lived in fully supported independent accommodation. A particular deficit in verbal communication was noted for all individuals. Five of the reported affected individuals (71%) met diagnostic criteria for autism or autism spectrum disorder: this diagnosis was based on features of repetitive movements and limited play and communication. All affected individuals were noted to be content and socially responsive, showing affection to and interest in their families. Hyperactivity was noted in four of the seven (57%).
- Hearing and vision: Four reported individuals (57%) had strabismus but none had a confirmed visual or hearing impairment.
- Seizure disorder: Three of the individuals developed a seizure disorder which could be controlled on medication.
- Neuroradiological changes: One individual had mild cortical atrophy [thinning of the appearance of the brain].
- Additional neurological features were described in all reported affected individuals. Low truncal tone, delayed motor milestones in the first year of life, and delayed onset of walking (age range to achieve independent ambulation: 2 to 5 years) was universal. When ambulant all had a wide-based, unsteady gait. Progressive neurological features were present in three individuals who had progressive spasticity, with one loosing independent ambulation in mid-childhood, and two individuals requiring a wheelchair or stroller for mobility outside of the home. In addition, one individual had a progressive neuropathy and in later childhood lost strength and reflexes in his legs. Two individuals were noted to have low sensitivity to pain, leading to self-sustained injuries. Unusual movements were described in six of the seven affected individuals: four had paroxysmal tongue movements (tongue thrusting or tremulous movements of the tongue), two had stereotypical [‘repetitive’] hand movements, one had head tics, and two had episodes of whole-body hypertonicity, which was not consistent with a seizure.
- Microcephaly: three of the affected individuals had progressive microcephaly. Other growth parameters were generally in the normal range.
- Gastrointestinal symptoms: Feeding difficulties, failure to thrive, or gastro-esophageal reflux were reported as significant for six individuals, with two individuals requiring fundoplication/gastrostomy.
- Facial features: Individual appearance is non dysmorphic. When assessed as a group, some similarity in facial features was apparent, particularly at younger ages, including fine, arched eyebrows, a short nose with depressed bridge and blunt tip, broad columella, a thick everted lower lip, widely spaced teeth, downturned corners to mouth, mouth often held open, and esotropia. None of the affected individuals with the p.Arg913Ter variant had the midline clefting, parietal foramina or extreme hypertelorism characteristic of affected individuals with the p.Arg1163Trp variant. Two of the three older male individuals had progressive coarsening of their facial features.