De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features

Mari J. Tokita; Chun-An Chen; David Chitayat; Ellen Macnamara; Jill A. Rosenfeld; Neil Hanchard; Andrea M. Lewis; Chester W. Brown; Ronit Marom; Yunru Shao; Danica Novacic; Lynne Wolfe; Colleen Wahl; Cynthia J. Tifft; Camilo Toro; Jonathan A. Bernstein; Caitlin L. Hale; Julia Silver; Louanne Hudgins; Amitha Ananth; Andrea Hanson-Kahn; Shirley Shuster; Undiagnosed Diseases Network; Pilar L. Magoulas; Vipulkumar N. Patel; Wenmiao Zhu; Stella M. Chen; Yanjun Jiang; Pengfei Liu; Christine M. Eng; Dominyka Batkovskyte; Alberto di Ronza; Marco Sardiello; Brendan H. Lee; Christian P. Schaaf; Yaping Yang; Xia Wang

doi:10.1016/j.ajhg.2018.06.005

PMC full text:

Am J Hum Genet. 2018 Jul 5; 103(1): 154–162.

Published online 2018 Jun 28. doi: 10.1016/j.ajhg.2018.06.005

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Table 1

Key Clinical Characteristics of Subjects with TRAF7 Variants

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Subject 6	Subject 7
Age	7.5 years	3 weeks	43 years	28 months	1 week	20 months	8 years
Sex	male	male	male	female	male	female	male
Variant	p.Arg655Gln	p.Arg655Gln	p.Arg655Gln	p.Arg655Gln	p.Thr601Ala	p.Lys346Glu	p.Arg371Gly
Number of mutant/total reads by exome sequencing	98/207	56/107	188/390	56/120	192/411	75/136	14/105
Prenatal ultrasound findings	choroid plexus cyst, two-vessel cord	cystic hygroma, cardiac defect, two-vessel cord	none	dichorionic/diamniotic twin pregnancy, cardiac defect	cardiac defect, sloped forehead, redundant nuchal skin, bell-shaped chest	none	cystic hygroma, IUGR
Postnatal concerns	respiratory distress, poor feeding, hypotonia	respiratory distress	hypersomnia, poor feeding	respiratory distress	cardiopulmonary arrest; ECMO complicated by intracranial hemorrhage	respiratory distress with pulmonary edema, jaundice	increased sleepiness, poor feeding, jaundice
Development
Motor delay	yes	n/a	yes	yes	n/a	no	normal then regressed
Speech delay	yes	n/a	yes	yes	n/a	yes	normal then regressed, severe autism
Neurologic features
Tone	hyper/hypotonia	hypertonia	leg stiffness	normal	hypotonia	normal	normal
Seizures	no	no	yes	no	no	staring spells, possible absence seizures	yes
Dysmorphic features
Multiple hair whorls	yes	no	no	no	yes	no	yes
Ptosis	yes	yes	no	yes	no	no	yes
Epicanthal folds	yes	yes	no	yes	no	yes	yes
Abnormally set or dysplastic ears	yes	yes	yes	yes	yes	yes	no
Low hairline or excess nuchal skin	yes	yes	no	yes	yes	no	yes
Wide-spaced or inverted nipples	yes	yes	no	yes	yes	no	yes
Umbilical hernia or diastasis recti	yes	yes	no	yes	no	no	no
Structural findings on neuroimaging	hydrocephalus, variant venous anatomy, abnormally shaped corpus callosum and cerebellum	mildly prominent ventricles and extra cerebral spaces	syringohydromyelia of C5-T12	cerebral greater than cerebellar atrophy	normal	possible sulcal/gyral asymmetry in right frontal/parietal region, mild cortical irregularity	prominent anterior and posterior horns of left lateral ventricle, variant venous anatomy
Echocardiogram findings	supravalvular pulmonary stenosis, PDA; incomplete right bundle branch block	severe aortic coarctation, parachute mitral valve, supravalvular mitral ring, PDA, small VSD, hypoplastic left ventricle	bicuspid aortic valve, small ASD, PDA	DORV, pulmonary atresia, hypoplastic left heart, aortopulmonary collaterals, RVH	DORV, mitral atresia, univentricular physiology	bicuspid aortic valve, moderate aortic valve stenosis, large PDA; prolonged QT	none
Digital anomalies
Overlapping digits	yes	yes	yes	no	yes	yes	no
Variant creases	yes	yes	no	yes	yes	yes	yes
Clinodactyly	no	yes	no	no	yes	no	yes
Contractures	yes	no	yes	no	no	no	no

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Abbreviations: IUGR, intrauterine growth restriction; n/a, not ascertained; PDA, patent ductus arteriosus; ASD, atrial septal defect; VSD, ventricular septal defect; DORV, double outlet right ventricle; RVH, right ventricular hypertrophy; ECMO, extracorporeal membrane oxygen.