De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Vetrini, Francesco; McKee, Shane; Rosenfeld, Jill A.; Suri, Mohnish; Lewis, Andrea M.; Nugent, Kimberly Margaret; Roeder, Elizabeth; Littlejohn, Rebecca O.; Holder, Sue; Zhu, Wenmiao; Alaimo, Joseph T.; Graham, Brett; Harris, Jill M.; Gibson, James B.; Pastore, Matthew; McBride, Kim L.; Komara, Makanko; Al-Gazali, Lihadh; Al Shamsi, Aisha; Fanning, Elizabeth A.; Wierenga, Klaas J.; Scott, Daryl A.; Ben-Neriah, Ziva; Meiner, Vardiella; Cassuto, Hanoch; Elpeleg, Orly; Holder, J. Lloyd; Burrage, Lindsay C.; Seaver, Laurie H.; Van Maldergem, Lionel; Mahida, Sonal; Soul, Janet S.; Marlatt, Margaret; Matyakhina, Ludmila; Vogt, Julie; Gold, June-Anne; Park, Soo-Mi; Varghese, Vinod; Lampe, Anne K.; Kumar, Ajith; Lees, Melissa; Holder-Espinasse, Muriel; McConnell, Vivienne; Bernhard, Birgitta; Blair, Ed; Harrison, Victoria; Muzny, Donna M.; Gibbs, Richard A.; Elsea, Sarah H.; Posey, Jennifer E.; Bi, Weimin; Lalani, Seema; Xia, Fan; Yang, Yaping; Eng, Christine M.; Lupski, James R.; Liu, Pengfei

doi:10.1186/s13073-019-0623-0

Table 1 Phenotypic data in individuals with TCF20 mutations

From: De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Subject	Age/sex	ID	Neurobehavioral abnormalities	Dysmorphic facial features	Sleep disturbance	Macrocephaly	Overgrowth	Digital anomalies	Seizures	Motor delay	Hypotonia	Movement disorder	Language delay	Structural brain abnormalities	Other features, additional variants detected
#1	3 y M	+	NR	Coarse facies, wide nasal bridge, long eyelashes, tented upper lip	NR	−	−	NR	Nocturnal epilepsy	+	NR	NR	+	NR	Duplicated left kidney, atrial septal defect, tethered spinal cord, dilated coronary artery
#2^a DDD_269612	14.3 y F	+	NR	Frontal bossing, full cheeks	NR	−	+	Long fingers with contracture of 5th finger, long toes	NR	+	NR	NR	+	NR	Joint hypermobility, increased carrying angle
#3	20 y M	NR	ASD, ADHD, anxiety	NR	NR	Borderline	+	NR	NR	+	Congenital	Dyspraxia	+	NR	NR
#4	3.25 y M	NR	ASD	Frontal bossing, triangular face	+	+	NR	NR	NR	+	NR	Visuo spatial perception difficulty, dyspraxia	NR	NR	NR
# 5 DDD_277986	8.5 y M	Moderate	NR	Mild dysmorphic facial features with depressed nasal bridge	NR	−	−	NR	NR	Severe	+	NR	Severe	NR	Feeding difficulties (tube fed)
#6	10.2 y M	+	ASD	NR	NR	NR	−	NR	Complex partial intractable	+	Congenital	Ataxia	Severe expressive/mild receptive	Mild cerebellar atrophy	Growth retardation, short stature, type 2 fiber muscular atrophy, laryngeal cleft, recurrent otitis media
#7^b	10 y M	+	ASD, ADHD, anxiety, self-harming behavior	Mild	−	−	−	Tapered 5th fingers with minor cutaneous 2–3 to syndactyly	Epileptic disorder with multifocal origin	+	Congenital generalized	NR	+	NR	De novo c.1189C>T, p.Gln397* in SLC6A1
#8^a DDD_274421	6.9 y M	+	ADHD	Abnormal hair whorl	+	−	NR	NR	+	+	NR	NR	+	NR	NR
#9 DDD_267241	11.9 y M	+	ADHD, obsessive–compulsive trait	Brachycephaly, low-set ears	NR	−	−	Finger-tip pads, sandal gap, clinodactyly of the 5th toe	NR	−	NR	Abnormal movement	−	NR	Inverted nipples, feeding difficulties, microcephaly
#10^a DDD_261665	11.5 y F	Moderate	Obsessive compulsive, food-seeking, aggression	Abnormal facial shape	+	+	Overweight	NR	NR	Moderate	+	NR	Severe receptive and expressive	NR	NR
#11	3.9 y M	+	ASD	Deep-set eyes, hypertelorism, long philtrum, tented upper lips, wide mouth, full lips, mild coarsening	+	+	−	NR	NR	+	Congenital generalized	Distal spasticity	Severe expressive/receptive	−	NR
#12 DDD_305239	3 y F	NR	ASD	USPFs, epicanthus, short nose, depressed nasal bridge, short lingual frenulum	+	−	−	NR	NR	+	NR	NR	+	NR	NR
#13	1.2 y M	+	NR	Plagiocephaly, epicantal folds, depressed nasal roots, tented upper lip	+	NR	NR	5th finger clinodactyly	NR	+	NR	NR	+	NR	NR
# 14 DDD_284745	7.9 y F	Mild	Hyperactivity	USPFs, anteverted nares	NR	−	−	5th finger clinodactyly	Febrile seizures	Mild	Mild	Motor coordination disorder	Mild	NR	Oligohydramnios on 20 weeks scan, ptosis, drooling, fatigue
# 15 DDD_274474	2.5 y F	NR	NR	Brachycephaly, myopathic facies, depressed nasal bridge, anteverted nares, open mouth with downturned angles	NR	−	−	NR	NR	+	+	Gait ataxia	+	NR	NR
#16 DDD_285718	6.5 y M	Mild	ASD, ADHD	NR	NR	−	−	NR	NR	Moderate	+	−	Moderate	+	NR
#17^b	5.4 y F	+	ASD, self-injurious, aggression, hyperactivity, food-seeking behavior	Midface hypoplasia, bulbous nose, tented upper lips	+	−	−	NR	NR	+	Congenital generalized	NR	Severe expressive/receptive	NR	De novo c.1307G>T (p.R436L) in ZBTB18
#18 DDD_286061	9 y F	+	Hyperactivity	High anterior hairline, large and tall forehead, temporal hypotrichosis, low-set, posteriorly rotated ears, broad philtrum, narrow mouth	NR	−	−	Broad hallux, 2–3 toe syndactyly	NR	+	+	NR	+	NR	Strabismus, joint hypermobility, drooling
#19^a DDD_266071	10.2 y M	NR	ASD, hyperactivity	Brachycephaly	NR	−	Tall stature	Contracture of 5th finger	+	+	NR	Paroxysmal dyskinesia	+	NR	High-pitched voice, ichthyosis (due STS deficiency)
#20	8.1 y M	+	NR	−	+	NR	NR	NR	NR	Mild	Congenital generalized	Impaired coordination, increased tone at the elbows	Expressive	NR	NR
#21 DDD_304759	33.3 y M	Moderate	NR	NR	NR	−	Tall stature	NR	NR	NR	NR	NR	NR	NR	High-pitched voice
#22 DDD_299802	9.9 y F	Severe	NR	Deep-set eyes, full cheeks, long face, tall forehead, prominent lower lip and chin, sunken eyes	NR	+	+	Slender fingers	NR	+	+	Jerky movements	+	NR	Hypermetropia, amblyopia
#23 DDD_304749	4 y M	NR	ASD	Broad forehead, short nose, depressed nasal bridge	NR	−	−	NR	NR	+	NR	NR	+	+	Inverted nipples
#24 DDD_300882	7.8 y M	NR	ASD	Low-set ears	NR	−	−	NR	+	+	NR	NR	+	NR	NR
#25	5.3 y F	+	ASD	Mild	+	−	−	NR	NR	Mild	Congenital generalized	NR	Severe expressive	NR	Hypohidrosis
#26 ^a DDD_261626	3.1 y F	NR	ASD	Long eyelashes, DSPFs, epicanthic folds, everted lower lip, open mouth	NR	−	−	Tapered fingers	NR	+	+	NR	NR	Delayed CNS myelination and lack of cerebral white matter	NR
#27 DDD_294521	17 y M	Moderate	−	Plagiocephaly, bilateral ptosis, horizontal crus of helix, malar flattening, narrow mouth	NR	−	Truncal obesity	Short, tapering fingers with incurved 5th fingers, mild bilateral hallux valgus	−	Mild	+	Motor coordination difficulties	+	Right posterior plagiocephaly	Inverted nipples
#28 DDD_294521.	17 y M	Moderate	−	Plagiocephaly, bilateral ptosis, horizontal crus of helix, malar flattening, narrow mouth	NR	−	Truncal obesity	Short, tapering fingers with incurved 5th fingers, mild bilateral hallux valgus	−	Mild	+	Motor coordination difficulties	+	Right posterior plagiocephaly	Inverted nipples, High arched palate
#29	4 y F	+	Repetitive behavior, ASD,ADHD	NR	+	−	−	NR	NR	Mild	Congenital generalized	NR	Mixed severe expressive/receptive	NR	NR
#30	14 y M	+	active autistic disorder	+	+	+	NR	NR	NR	Mild	Congenital generalized	NR	+	NR	Scoliosis
#31	5 y M	+	NR	NR	NR	+	+	NR	+	+	Congenital generalized	Balance disorder	+	NR	NR
#32	1.1 y F	+	Autistic features, food-seeking behavior	Midface hypoplasia, long eyelashes, thick lips, occipital groove	+	+	NR	NR	NR	+	Mild generalized	Mild spasticity in ankle dorsiflexors	Significant expressive/receptive	Cavum septum pellucidum and vergae	Dysphagia, GERD, renal cyst, delayed visual maturation
Schafgen et al. [14]; Babbs et al. [6]; Lelieveld et al. [15]; McRae et al. [16]*	n = 2 (12–14 y, M); n = 4 (n = 3F, 1 M); n = 6 (NR)	Mild to moderate (n = 8/12)	Autistic features (n = 5/12), stereotypic behavior (n = 1/12), aggression (n = 1/12)	n = 4/12	NR	n = 3/12	n = 2/12	n = 1/12	n = 1/12	n = 5/12	n = 3/12	NR	n = 5/12	Abnormality of the cerebrum n = 2/12	Inverted nipples (n = 2/12), tapered fingers (n = 1/12), small penis (n = 1/12), abnormal eye physiology (n = 1/12), abnormality of the mouth (n = 1/12)

Abbreviations: ID intellectual disability, M male, F female, y year old, NR not reported, N/A not applicable, + present feature, − absent feature, ASD autism spectrum disorder, ADHD attention-deficit hyperactivity disorder, FTT failure to thrive, USPF upslanting palpebral fissures, DSPF downslanting palpebral fissures, IUGR, intrauterine growth retardation, GERD gastro-esophageal reflux disorder
^aFive patients from the original McRae et al. DDD cohort [16] (individual #2, #8, #10, #19, and #26) were included in this study
^bThe clinical phenotype in subjects #7 and #17 might result from a combination of TCF20 variants and additional contributions in variants detected in SLC6A1 and ZBTB18, respectively
*Two additional patients from this study were included in the meta-analysis from previous studies

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