TABLE 2.

Neurodevelopmental and dysmorphic features of patients with variants in BPTF

ID	Variant	Sex	Age	DD/ID	Speech delay	Motor delay	Hypotonia	Autism	ADHD	Dysmorphic features	Eye anomalies	Skeletal anomalies	Brain anomalies	Seizures and/or EEG abnormalities	Other comments
Patient 1	c.209dupG (p.Ser71Glnfs*3)	F	23 months	+	+	+	+	N/A	N/A	Bilateral epicanthal folds, slightly short palpebral fissures, tubular nose, flat cheekbones, fetal fingertip pads, mild 2–3 syndactyly of the feet, borderline low tone	>Bilateral myopia with astigmatism	N/A	Minimal asymmetry of the temporal horn of the right lateral ventricle; no other intracranial pathology.	Diagnosed with epilepsy and has generalized tonic–clonic seizures as well as staring spells.	History of feeding difficulties with oral aversion, GERD, poor weight gain and constipation. Diagnosed with global developmental delay (DQ =
Patient 2 (mother of Patient 1)	c.209dupG (p.Ser71Glnfs*3)	F	N/A	+	+	+	N/A	N/A	N/A	Short and narrow palpebral fissures, prominent nasal ridge, broad great toes.	Exotropia	N/A	N/A	N/A	SGA at delivery, delayed walking and talking; described as a “poor eater.” Difficulties in school and repeated kindergarten twice. Intellectual ability in the “borderline range” per school testing. Is generally able to manage her own affairs but needs assistance with some tasks like paying bills.
Patient 3	c.255delC (p.Ser86Alafs*151)	F	22 years	+	+	+	+	+	+	Prominent nasal ridge, thin upper lip	N/A	N/A	N/A	N/A	Hypothyroidism, poor weight gain and decreased growth velocity; anxiety, depression; recurrent oral ulcers. Required inclusion classroom with 40% special education; now resides in a group home. First words said on time but did not progress normally. Now able to speak in sentences and is able to write.
Patient 4	c.255delC (p.Ser86Alafs*151)	M	7 years 1 month	+	+	N/A	+	N/A	N/A	N/A	None	N/A	N/A	N/A	N/A
Patient 5	c.255dupC (p.Ser86Glnfs*43)	F	10 years	+	+	+	−	N/A	N/A	Triangular‐shaped face, café au lait macules (left medial calf 2.5 cm × 1 cm, left ASIS 7 mm, right anterior chest‐abdomen 5 mm, left anterior chest 3 mm, right lateral thigh 1 cm × 1.5 cm, left lateral hip 7 mm)	Intermittent exotropia, emmetropia	S‐shaped scoliosis of the thoracolumbar spine; mild kyphotic deformity of the thoracic spine; mild anterior wedging of mid‐thoracic vertebra; length discrepancy of arms (right arm longer than left arm by about 5–7 mm)	Normal brain MRI	N/A	Poor weight gain/failure to thrive; in utero growth retardation; increased muscle fatigability and abnormal fingers usage; mild elevation of LDL and mildly depressed HDL
Patient 6	c.1282G > T (p.Glu428*)	M	13 years	+ (mild)	+ (mild)	+	+	N/A	N/A	Long nasal bridge, retrognathia, high palate	N/A	N/A	Small venous anomaly of right front; no other abnormality	Epilepsy requiring sodium valproate	Recurrent fevers, oral ulcers, skin rashes, initially requiring treatment now improved; dysphonia
Patient 7	c.1607_1620del (p.Asp536Glyfs*5)	M	12 years 8 months	+ (mild)	+	−	−	N/A	+	Metopic ridge, brachycephaly, mild micrognathia, synophrys, apparently long tongue, cutis marmorata; square finger tips, moderate soft tissue syndactyly of toes 2 and 3, broad great toes and thumbs, wide sandal gap deformities	Left convergent squint ‐ resolved	Very mild scoliosis, delayed bone age (3 months at 18 months; normalized at age 8), metopic synostosis; prominent lumbar lordosis	Normal brain MRI	N/A	Constipation, hypertonia (~age 12), with brisk reflexes and clonus, recurrent facial nerve palsy (age 5‐6 years); pupillary hippus, early dental caries, cutis marmorata and poor peripheral circulation
Patient 8	c.2724_2727del (p.Thr909Serfs*4)	F	2 years	+	+	+	−	N/A	N/A	Epicanthal folds, prominent pointed helices with prominent antihelices; prominent nasal root, mild bulbous nasal tip	Astigmatism, myopia, right eye exotropia	Broad great toes	Hypotelorism; otherwise unremarkable MRI of the brain	N/A	Little subcutaneous fat, feeding issues
Patient 9	c.2921+1G > C	M	14 years 3 months	+ (mild)	+ (mild)	+	+	N/A	N/A	Thin upper lip, wide mouth.	None	None	N/A	N/A	Initial failure to thrive requiring gastrostomy; recurrent bacterial infections as a young child, requiring regular immunoglobulin infusions until age 4 y. First walked at 2 years. In mainstream school with statement of special educational needs.
Patient 10 (mother of Patient 9)	c.2921+1G > C	F	N/A	−	−	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Patient 11	c.3085delA (p.Thr1029Glnfs*27)	N/A	N/A	+	N/A	N/A	N/A	N/A	N/A	Prominent nasal tip, high arched palate, brachycephaly, micrognathia, short stature.	“Weak” vision reported	Radioulnar stenosis	N/A	N/A	N/A
Patient 12	c.3210_3221del (p.Asn1071_Glu1074del)	M	11 years 1 month	+ (mild)	+	+	N/A	N/A	N/A	Right microtia with over‐folded helix, epicanthal folds, upslanting palpebral fissures, high palate, micrognathia, bulbous nasal tip; small body habitus (including hands and feet), fine hair on the back, one hyperpigmented and one hypopigmented macule	N/A	Right thumb is smaller than the left (4 cm vs. 3.9 cm); second toe is bent in a flexed position, but not contracted bilaterally; broad halluces	Normal brain MRI	N/A	Right microtia also seen in mother without BPTF variant
Patient 13 (father of Patient 12)	c.3210_3221del (p.Asn1071_Glu1074del)	M	55 years	+ (mild)	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	Mild delays in school, but employed.
Patient 14	c.3233_3237del (p.Arg1078Metfs*13)	M	8 years	+	+	+	−	+	N/A	Broad halluces, small chin, prominent columella, thin upper lip.	N/A	Delayed bone age (8 m)	N/A	N/A	IQ 60. Started talking around the age of 3 years.
Patient 15	c.3610C > T (p.Arg1204*)	M	4 years 6 months	+	+	+	−	−	−	N/A	N/A	N/A	Normal brain MRI	−	N/A
Patient 16 (mother of patient 15)	c.3610C > T (p.Arg1204*)	F	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Patient 17	c.4555C > T (p.Arg1519*)	F	9 years	+ (mild)	+	+	−	+	+	Lateral flaring of eyebrows, narrow palpebral fissures, prominent ears and cheekbones, small mouth, micrognathia	Transient strabismus when tired	Overlapping second toe on left foot, small sandal gap deformity of both feet	Normal brain MRI	Epileptic seizures treated with levetiracetam	Infantile autism, hyperhidrosis. IQ 70.
Patient 18	c.5936‐1G > A (p.Thr1980Glufs*25)	M	8 years 8 months	+ (mild)	+	+	−	N/A	N/A	Prominent forehead, prominent nasal bridge, mild malar hypoplasia, medial flaring of the eyebrows, telecanthus, mild retrognathia	None	Cutaneous syndactyly of hands (3–4) and feet (2–3) ‐ likely autosomal dominant syndactyly based on family history; mild pes planus, bulbous halluces	N/A	N/A	Severe feeding problems requiring gastrostomy; congenitally corrected transposition of the great arteries. Mild to moderate intellectual disability (IQ 57).
Patient 19	c.6078dupT (p.Ala2027Cysfs*2)	M	12 years	+	+	+	−	N/A	N/A	Micrognathia, dental crowding, midface hypoplasia, upslanting palpebral fissures	Left eye ptosis, limited peripheral vision, 20/25 vision	Leg length discrepancy, mild scoliosis, 2–3 syndactyly bilateral, tooth eruption at 2–4 m	Normal brain MRI	N/A	Bilateral polycystic kidneys diagnosed prenatally, constipation, unilateral cryptorchidism (left)
Patient 20	c.6259+3_6259 + 4delinsG	F	9 years	+ (mild)	+	+	+	N/A	N/A	Prominent long nose, micrognathia, lateral flaring of eyebrows	Unilateral exotropia	Thoracic kyphosis, sandal gap both feet, 2–3 syndactyly of both feet, broad great toes, long slender fingers	N/A	N/A	Hypermobility
Patient 21	c.7521_7524dupATCT (p.Leu2509Ilefs*21)	M	10 years	+ (mild)	+	+	+	N/A	N/A	Narrow face shape with mild retruded midface and slightly prominent metopic suture, subtle upslant of eyes with mild ptosis; epicanthal folds present, flat philtrum with thin lips. First toe bilaterally is slightly laterally deviated and a little bit broad	Stable hyperopia and alternating exotropia, wears glasses	Thoracolumbar scoliosis (improved ‐ previously required bracing) and leg length discrepancy; butterfly vertebra at T12 and questionable fusion of right posterolateral aspects of T5 and T6 vertebral bodies	Mild confluent T2/FLAIR hyperintense signal in the periatrial white matter, with associated slight prominence of adjacent atrium of lateral ventricles; probably represents sequelae of old insult	Complex focal seizures with impaired awareness of frontal lobe origin beginning at age 7 y, controlled by medication with recent vagal nerve stimulator placement	Significant failure to thrive and small for gestational age; severe bleeding problem after circumcision. Delays and mild intellectual disability (IQ of 52); spoke first words at 4 years, spoken language level is not age appropriate; walked at 16 months.
Patient 22 a	c.7875+3559_7876‐2789del and t(1;17)(q24.3;q24.2)	M	8 years	+	+	+	+	N/A	N/A	Prominent mid‐forehead, craniofacial asymmetry, asymmetric face, triangular shape, asymmetric zygomatic region, hypertelorism, proptosis, lateral flaring of the eyebrows, broad eyebrows, broad palpebral fissures, long eyelashes, long nasal bridge, prominent nose, broad nose tip, thin upper lip, micrognathia, microglossia, microgenia, retrogenia, high palate, crowded small teeth, protruding ears, different size of ears, asymmetric location of ears, large helices of both ears, low‐set or posteriorly rotated ears, prominent ears, anteriorly rotated left ear axis, broad tragus, small lobes	Myopia, strabismus, absence of binocular single vision and stereopsis	Scoliosis, narrowing intervertebral foramen and canal of lumbosacral part of spine L4‐L5‐S1, fifth finger clinodactyly, shorter phalanges of fifth fingers and halluces, bilateral partial 2–3 syndactyly, sandal gap deformities of both feet	Thickening of the bone of the skull's vault, the ssella turcica extended with a flat bottom, the anterior pituitary is uniformly enhanced after gadolinium administration, but there is decreased height of the gland (4 mm), upper surface of the anterior pituitary is flat, the L‐basilar artery is tortuous and elongated, but it is not widened; adheres to the brainstem with a small degree of brainstem compression, cortical and subcortical atrophy with widening of intracranial fluid spaces	N/A	Feeding difficulties, hyperhidrosis, delayed psychomotor development, deep feeling of both feet is incorrect, left ventricular failure, diabetes, hypercholesterolemia, decreased estradiol. Difficulties with comprehending the meaning of text, disturbances with recognition of mistakes in written text, difficulties with subtraction and operations performed on numbers of higher values; difficulties remembering items directly, learning difficulties, dyslexia and dysgraphia due to a defect of phonemic audition.
Patient 23	c.8081G > C (p.Arg2694Thr)	M	9 years	−	+ (mild)	−	−	N/A	N/A	N/A	None	None	N/A	N/A	Horseshoe kidney, VSD closed spontaneously
Patient 24	c.(7875 + 1_7876–1)_(8209+1_8210‐1)del	F	12 years 3 months	+	+	−	−	N/A	N/A	Mild facial dysmorphism—short palpebral fissures, thin upper lip lateral flaring of eyebrows	No	None	Normal brain MRI	EEG abnormalities, focal temporoparietal left, but no clinical seizures	Mild intellectual disability; IQ‐Test 2016:69 (HAWIK IV); First words at 2 years 3 months; still speaks in simple sentences. History of anxiety.
Patient 25	c.8210+6_8210+8del	F	2 years	+	+	+	+	N/A	N/A	Low set ears, slightly upslanting palpebral fissures, epicanthal folds, 3 small irregular café au lait macules, unilateral single palmar crease	Bilateral persistent pupillary membrane, unilateral iris coloboma, unilateral subtle subluxated lens	Sandal gap deformities	Normal brain MRI	N/A	Hypoplastic index finger nail/ nail bed. Developmental delay though no intellectual disability.
Patient 26	c.8278G > T (p.Glu2760*)	M	11 years	+	+	+	+ (mild)	N/A	N/A	Preauricular chondroma (unilateral), 3 café au lait macules	Exotropia of left eye, hypermetropia	N/A	N/A	EEG at 6y with spikes in right frontal region, enhanced by photic stimulation and sleep—no clinical seizures	Mild to moderate ID, did not meet criteria for autism although had stereotypies; first words at 3years; held head up at 9 monthsonths, sat at 15 months, walked at 20 months.

Abbreviation: N/A, not available or not reported.

^aPreviously reported (Midro et al., 1993, 2019).