Supplemental data S1
Clinical report:
Patient 1 was born, following an uncomplicated pregnancy, with a weight of 2.9 kg (10 th - 25 th centile), length of 53.3 cm (95 th centile), head circumference of 34.6 cm (25 th centile, -1 SD) and an
Apgar score of 8 (Table 1). As a neonate he had tremors, a delayed cry and appeared stiff. He fed poorly with recurrent vomiting, ultimately resulting in abdominal exploration, Nissen fundoplication and gastrostomy tube placement. He started walking at 27 months and had speech delay with a vocabulary of about 20 single words by 5 years. Seizures began at age 7 years, with recent seizures being of the grand mal type. Neurocognitive testing at age 8.5 years old showed an IQ of 41, in the severe intellectual disability range, and a behavioral pattern that falls within the autism spectrum. MRI demonstrated general atrophy of the brain with specific structural abnormalities including enlarged ventricles and subarachnoid spaces around the brain, small cerebellar vermis, thin corpus collosum, small brainstem, optic nerve hypoplasia, and global decrease of white matter.
At age 11-3/12 years, he had a weight of 32.2 kg (25 th centile), height of 138 cm (10 th - 25 th centile), and head circumference of 48.8 cm (<< 3 rd centile, -3.5 SD). Eyes were deep-set and narrowlyspaced with exotropia and down-slanting palpebral fissures (Figure 1A). His ears measured at 5.5 cm
(25 th centile) and were prominent and cupped, with a posterior pit in the superior helix bilaterally. He had a thin nose, long philtrum, thin upper lip, moderate micrognathia, pes planus, facial freckling, numerous small pigmented macules (less than 0.5 cm) elsewhere on his body, chronic eczema primarily localized to his knees, arms, hands and neck and bilateral fifth finger clinodactyly. He was hypoactive, weak, and has action tremors that began four years ago.
Patient 2 was born, following an uncomplicated pregnancy, with a weight of 2.72 kg (5 th - 10 th centile), length of 47 cm (5 th centile), head circumference of 32 cm (3 rd - 10 th centile, -1.5 SD) and an

Apgar score of 10 (Table 1). He had feeding difficulty at birth. Motor delays included sitting at 15 months and walking at 22 months. He had a slim body type, thin skin, pectus excavatum and arachnodactyly.
Dysmorphic features included thin eyebrows, poorly folded ears, a thin upper lip, and micrognathia
(Figure 1B). He spoke first words at 26 months, and his vocabulary remains very limited. Behavioral and neurocognitive symptoms included hyperactivity, anxiety, and severe cognitive impairment. He had hyperopia. MRI of the brain was normal.
Patient 3 was born following an uncomplicated pregnancy, with a weight of 3.28 kg (50 th centile), length of 49 cm (25 th centile), head circumference of 33 cm (10 th centile, -1.5 SD), and an Apgar score of 10 (Table 1). He was hypertonic, constipated and had difficulty feeding. Developmental delays included sitting at 12 months, walking at 23 months and speaking first words at 36 months. At age 3.5 years, his weight and length were 10 th centile, and head circumference was < 3 rd centile. Dysmorphic features included plagiocephaly, sparse hair, long and large eyebrows, poorly-folded ears with thick and folded helices, a short nose, long philtrum, a large mouth, a short neck, and bilateral transverse palmar creases (Figure 1C). He had severe cognitive impairment, stereotypies, and a sleep disorder. He had hyperopia and astigmatism. Brain MRI demonstrated partial hydrocephalus and a slight ventricle enlargement.
Patient 4 was the first child born to healthy parents. The fetus had delayed growth and diminished activity, with occasional brief periods of “intense movement.” The birth weight was 3.03 kg
(25 th centile), length 50 cm (50 th centile), and at 3 weeks, the head circumference was 33 cm (<3 rd centile, -2 SD). Development was globally delayed with walking at 18 months and first words at 18-24 months. Speech continued to lag with only 2 words at 41 months. He had exotropia and undescended testes. Tonic seizures associated with fever began at age 28 months. He preferred to play alone and avoided eye contact.

At 41 months, weight was 55 th centile, height was 50 th centile, and head circumference was 46.8 cm (<3 rd centile, - 2.5 SD). The eyes were deeply set, and the interpupillary measurement was 5 cm (25-
50 th centile; Figure 1D). The ears were cupped with prominence of the anthelices, excessive folding of the superior helices, and absence of ear lobes. The mandible, mouth, and tongue appeared small and the uvula was bifid. The glans penis was partially covered, the testes were at the inguinal ring, and the scrotum appeared flat. There was hyperextension at the elbows and knees, and the deep tendon reflexes at the right knee were greater than on the left.
At age 15 9/12 years, the height with some flexion at the hips and knees was 157.5 cm (<3 rd centile), weight 36 kg (<<3 rd centile) and head circumference 50.7 cm (<3 rd centile, -2.5 SD). He had no speech and had been diagnosed with autism. The hair was not sparse. Bitemporal narrowing was present. The ears measured 4.9 cm in length, had excessive overfolding of the superior helices, prominent anthelices and minimally developed lobes. The eyes were deep-set, the nose sharp and pointed, the upper lip thin and the chin small. He walked with flexion at the hips and knees.
Patient 5 was born at term, with a weight of 3.23 kg (25 th - 50th centile), length of 47cm (5 th centile) and head circumference of 31 cm (<3 rd centile; -2SD), to a healthy 36 year-old mother and 38 year-old father. The pregnancy was uncomplicated aside from somewhat decreased fetal activity in comparison to the mother’s previous pregnancy. At birth, the patient was noted to have undescended testes and hyperekplexia. He had a Nissen fundoplication and gastric tube in the first month for reflux.
He had chronic ear infections and was hospitalized for hematochezia. He started to sit and walk at age
23 months.
At age 6 years, his weight was <3 rd centile, height was 10 th to 25 th centile, and head circumference was 44.9 cm (<<3 rd centile, -5 SD). He had a duplicated left fifth toe with two nails. He had sparse hair, especially on the sides of his scalp, and his ears were mildly protruding bilaterally (Figure

1E). He had deep-set eyes and bilateral lacrimal duct stenosis. EEG showed generalized 3-4 hertz spikewave discharges. Brain MRI showed a slightly prominent ventricular system. He was diagnosed with moderate autism. He has had febrile seizures as well as some nonfebrile seizures in the past. He lacked spontaneous words but did have nonspecific vocalizations.
Patient 6 was born at 39 weeks after induction for intrauterine growth restriction. He had a weight of 3.40 kg (25 th - 50 th centile), length of 46 cm (3 rd centile) and head circumference of 35 cm (50 th
- 75 th centile; thought to be an overestimate because of a cephalohematoma) and a single umbilical artery. Postnatal studies included a normal blood karyotype and a renal ultrasound that showed a unilateral renal cyst (6 mm). Skeletal radiographs and head ultrasound were normal. Head MRI at 3 months was normal. Subsequent weights and lengths were within the normal range, while head circumference was -2 SD at 2 months and -4 SD at 11 months. He was very hypotonic. He sat alone at 18 months and started walking at 28 months. He had no language at age 3.5 years. Febrile seizures occurred at 6 months, responsive to Valproic acid.
At age 3.5 years, his weight was <3 rd centile, height was 10 th centile, and head circumference was 45 cm (<3 rd centile, -4 SD). He had deep-set, narrowly-spaced eyes with hyperopia, down-slanting palpebral fissures, synophrys, a thin upper lip, and moderate micrognathia. His ears were small with hypoplastic lobes. He had bilateral transverse palmar creases, and clinodactyly of the 5 th finger. He had moderate ataxia without dysmetria or tremor.
Patient 7 was born at term with a weight of 2.45 kg (3 rd centile), length of 47 cm (10 head circumference of 31 cm (3 rd centile, -2.5 SD), and an Apgar score of 10. Third trimester th centile), ultrasonography identified IUGR (<3 rd centile) and a single umbilical artery. MRI at 36 weeks postmenstrual showed “a brain biometry corresponding to a fetus of 32 weeks.” No brain malformations were identified. She had recurrent urinary infections (pyelonephritis) due to “a dilation of the urinary

tract” that started at age 1. During the first 2 years, she was hypotonic. She started walking at 27 months and had a vocabulary of about 20 single words by 6 years. First febrile seizures occurred at age 2 years. Atypical absence seizures responsive to Valproic acid were diagnosed after age 5 years. MRI showed a reduced volume of the brain either at the supratentorial or the infratentorial level with poorly developed white matter and thin optic nerves but no ventricle enlargement.
At age 6.5 years, her weight was 19.5 kg (25 th centile), height was 110 cm (5 th centile), and head circumference was 45 cm (<<3 rd centile, -5 SD). She had deep-set eyes and the appearance of hypotelorism. She had large ears with hypoplastic earlobes, a small and thin upper lip, and 5 th finger clinodactyly. She had very dry, blonde hair. Her skin appeared thin with two small macules (<0.5cm), one pigmented and one hypo-pigmented. She had hyperactivity and ataxia without dysmetria or tremor. She could not perform neuropsychological testing.
Patient 8 was the second child from healthy, non-consanguineous Caucasian parents. He was born at 41 weeks with a weight of 3.29 kg (10 th - 25 th centile), length of 47 cm (<3 rd centile), head circumference of 34 cm (25 th centile, -1 SD) and Apgar score of 8. In the neonatal period, he had feeding difficulties, generalized hypertonia, hypocalcemia, and a ventricular septal defect. G-tube feeding was required until age 3 years. He had recurrent vomiting. First febrile seizures occurred at 7 months and were treated with Valproic acid. He sat at 8 months, began to walk at 18 months, and did not have oral language at age 3 years. Brain MRI demonstrated general atrophy with enlarged ventricles, a septum pellucidum cyst, and thin brainstem. An eye exam showed optic nerve hypoplasia. Head circumference increased slowly and was below the 3 rd centile at 6 months. At age 3 years, head circumference was at -
4 SD, with weight and length at -1 SD. He had hand stereotypies, poor eye contact, and dysmorphic features including deep-set eyes, pointed nasal tip, micrognathia, small mouth with thin upper lip, large and low-set ears, and very slow-growing hair. Skin and male genitalia were normal.

Patient 9 was the first child of non-consanguineous young healthy parents. She had an asymptomatic younger brother. Pregnancy was unremarkable, and she was born at full term with a weight of 3.0 kg (25 th centile), length of 48 cm (25 th centile) and head circumference of 32 cm (3 rd centile, -2 SD). Apgar was 8/9. Neonatal period was unremarkable. Epileptic manifestation began at age
3 months with absences. At age 9 months, epileptic manifestations were infantile spasms. EEG recurrently diagnosed a 7-8 hz basal rhythm with several asymptomatic bi-frontal spikes and waves.
There was a major delay in gross milestones. Walking was acquired at age 4 years, and speech was absent. Behavioral troubles included auto-aggression, stereotypies, and sleeping disorder with early awakening. Nevertheless, she was affectionate and curious. Last clinical examination was performed at age 32 years. Height was 162 cm (45 th centile), weight 68 kg (60 th centile) and head circumference 53.5 cm (25 th centile; -1.5 SD). Facial dysmorphism was reported with low anterior hairline, horizontal eyebrows, deep-set eyes, low implanted columella, narrow ears, enamel dysplasia and crowded teeth
(Figure 1F). Neurological examination identified an intentional tremor and enlarged walking steps.
Paraclinical investigation included normal echocardiography, abdominal ultrasound and encephalic MRI.
Patient 10 was the third child born to non-consanguineous parents, with no familial history of cognitive deficits. Her father presents with ataxia, myotonia and muscle contractures of unknown etiology. She was born following an uncomplicated pregnancy although the fetus appeared particularly poorly active, and with a small weight of 2.22 kg (<3 rd centile), length of 46 cm (3 rd - 5 th centile) and a head circumference of 32 cm (3 rd centile, -2 SD; Table 1). At 26 months old, she had significantly delayed weight gain with a weight of 9.1 kg (<3 rd centile), height of 82.5 cm (10 th - 25 th centile) and head circumference of 43.5 cm (<<3 rd centile, -4 SD). She had notable feeding difficulties at birth, refusing breast-feeding and continued to have poor appetite at 26 months old. She presented with global developmental delay, with walking at 20 months and absence of speech. She had low-set and horizontal eyebrows, deep-set eyes, enopthalmos, thin and brittle hair, back hypertrichosis, and clinodactyly of the

5 th finger on the left hand. She had her first tonic-clonic epileptic episode at age 22 months. Brain MRI revealed discrete cerebellar atrophy associated with ventricular dilation, and asymmetric hyperintensities of the white matter.
At age 5 years her language was severely delayed with a vocabulary of 10 words. Her memory was good. She had generalized motor delay. The occurrence of epileptic episodes had been dramatically reduced with combined treatment of Lamotrigin and Valproate. She had a long nose with a pointed nasal tip, deep-set eyes with very low-set eyebrows and low-set and dysplastic ears with absent ear lobes (Figure 1G).