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. 2018 Dec 6;103(6):948–967. doi: 10.1016/j.ajhg.2018.11.001

Table 1.

Clinical Highlights of Affected Family Members with TMEM94 Variants

Features Family 1 Family 2 Family 3 Family 4 Family 5 Family 6
Position in the pedigree II.1 II.4 II.1 II.2 II.3 II.1 II.1 II.2 II.3 II.2
Ethnicity Omani Qatari European American Indian Turkish Egypt
Consanguinity + + No + Not reported, but parents from two small villages 3km away +
Variant in cDNA∗ and protein level c.2764C>T; p.Arg922∗ c.840del; p.Asp280Glufs∗10 c.2635dup; p.Met879Asnfs∗18 and c.795-1G>C c.2000_2004dup; p.Pro669Alafs∗8 c.4028+5G>A; p.Val1344∗ c.3497delA; p.Asn1166Thrfs∗84
Age 8 years 7 months 8 months 8 years 6 years 3 years 17 years 3 years 5 months 24 years 18 years 30 months
Gender Female Male Female Female Male Male Male Female Female Female
Growth Birth weight Not available 2.9 kg (born at 32 weeks age of gestation) (>97th centile) 1.77 kg (born at 30 weeks age of gestation) (90th centile) 4.36 kg (95th centile) 4.02 kg (born at 38 weeks of gestation) (85th centile) 4.65 kg (99th centile) 4.6 kg (> 97th centile) 3.7 kg (96th centile) Cesarean at 37 weeks 4.17 kg (>97th centile; +2.35SD) Cesarean section at 37 weeks 5/7 Not available
Birth length Not available Not available 45.5 cm (born at 30 weeks age of gestation) (>97th centile) 54 cm (98th centile) 55 cm (98th centile) Not available Not available 51cm (50-75th centile) 52cm (75th centile) Not available
Birth head circumference Not available Not available 26.5 cm (born at 30 weeks age of gestation) (50th centile) 37 cm (98th centile) 35 cm (50th centile) Not available Not available 33.5cm (25-50th centile) Not available Not available
Recent height 120 cm (10thcentile) 73 cm (75- 90th centile) 129.6 cm (75.76th centile) 124.3 cm (85th centile) 90 cm at 90th centile 188.0 cm (96th centile) 108 cm (>97th centile) 173cm (90-97th centile; +1.5SD), 178.1cm (>97th centile; +2.3 SD) at age 16yrs 95 cm (96th centile)
Recent weight 19 kg (<3rd centile) 8.3 kg (10- 25th centile) 25.7kg (61.08th centile) 22.4kg (65.7th centile) 17kg (88.74th centile) 79.5kg (91st centile) 17 kg (90-95th centile) 97kg (>97th centile; 2.89SD) 89.1kg (>97th centile; +2.51 SD) at age 16yrs 14.3kg (86th centile)
Recent head circumference 50 cm (<10th centile) 42 cm (< 3rd centile) 53.5 cm (90th centile) 55 cm (97th centile) 46.5 cm (77.38th centile) (at 10 months) 63.5 cm (>100th centile) 50.2 cm (75th centile) 58.5cm (>97th centile; +2.35SD) 58.5cm (97th centile; +2.35SD) 52cm (99th centile)
Neurologic features Motor delay (HP:0001270) + + + − + + + + + +
Learning disability (HP:0001328) + + + + + + + + + +
Speech delay (HP:0000750) + + + + + Expressive language delay + + + +
MRI o Normal brain MRI Normal brain MRI Not available Normal brain MRI Bilateral symmetrical restricted diffusion and high T2 signal intensity of the cerebral white matter of the brain Chiari type I malformation and cortical-based mass in the left inferior frontal gyrus pars orbitalis (ganglioglioma or other low grade glial tumor). Spinal MRI -T7 hyperintense signal Not available Not available Enhanced signal within both hippocampi in FLAIR cuts, signs of microhemorrhages, possibly linked to hemodynamic changes during heart surgery Not available
Facial features Triangular face (HP:0000325) + + + + + + + + + +
Hypertrichosis (HP:0004554) + + + + + + + + + +
Pointed chin (HP:0000307) + + + + + + + + + +
Synophrys (HP:0000664) + + + + + + + + + +
Thick arched eyebrows (HP:0002553) + + + + + + + + + +
Short nose (HP:0003196) + + + + + + + Prominent (HP: 0000448) Prominent (HP: 0000448) +
Flat nasal bridge (HP:0005280) + + + + + + + − − +
Long philtrum (HP:0000343) + + + + + - + HP:0000322 short philtrum HP:0000322 short philtrum +
Thin upper lip vermillion (HP:0000343) + + + + Triangular upper lip Not noted + prominent cupid bow upper lip, increased volume of lip vermillion prominent cupid bow upper lip, increased volume of lip vermillion +
Ears Low set ears (HP:0000369) + + + + + Posteriorly rotated low set ears with hypoplastic helices Large, low set posteriorly rotated ears HP:0008544, under folded helix HP:0008544, under folded helix +
Prominent ear lobules (HP:0009748) + + + + + + + + + +
Ophthalmological features No gross eye abnormalities, no extraocular muscle weakness, visual acuity not tested but no corrective lenses at time of examination No gross eye abnormalities, no extraocular muscle weakness, visual acuity not f tested but no corrective lenses at time of examination Quiet anterior segment, Normal fundus, Visual acuity: left eye (6/12), right eye (6/18), Need glasses (+0.5-1.75) Quiet anterior segment, Normal fundus, Visual acuity: left eye (6/9), right eye (6/9), Unaided Bilateral nystagmus, Normal fundus, Need glasses (-1.5, -1.75) Strabismus, deep set eye, long eye lashes, optic glioma of the right eye Refractive error, normal fundus Strabismus and myopia Visual acuity not formally tested but no need for corrective lenses at time of examination; HPO:0007838 progressive Ptosis Not available
Cardiac abnormalities Atrial septal defect Tetralogy of Fallot and pulmonary atresia None Small secondum ASD, two midmuscular VSDs and mall PDA (VSDs and PDA closed spontaneously) Small patent foramen ovale and VSD ASD, VSD, and PDA (PDA closed spontaneously); dilation of the ascending aorta (Z +3.6), sinus tachycardia, lymphatic vessel neoplasm Tetralogy of Fallot with hypoplastic pulmonary annulus, large peri membranous malaligned VSD and large secundum ASD AVSD, PDA, parachute mitral valve ASD, VSD, double outlet right ventricle without pulmonal stenosis ASD, VSD, Double outlet double ventricle
Skeletal features Long fingers and toes None None Mild scoliosis None Severe scoliosis, arachnodactyly, large hands, bilateral overlapping of the 3rd toe by the 2nd and 4th toes, asymmetry of the hip, osteochondroma of the proximal left tibial metaphysis Bilateral overlapping toes, bilateral long great toes Open bite and prognathism, long fingers, narrow hands (palm width/length- 2.75SD) Thoracic kyphoscoliosis, long fingers, bilateral cutaneous 2,3 toe syndactyly, overlapping of the 2nd toe by the 3rd toe, narrow hands (palm width/length -3SD) Not available
Respiratory features None None Bronchial asthma, recurrent infections Wheezy chest, bronchomalacia Neutropenia, recurrent infections Laryngotracheomalacia, dyspnea, recurrent pneumonia None None None None
Gastrointestinal features None None None None None GERD, mesenteric cyst, diarrhea, constipation None Omphalocele and malrotation None Not available
Genitourinary features None None None None None Mullerian duct remnant, adrenal cyst, dysuria, urinary retention, bilateral inguinal hernia Penile hypospadias, bilateral undescended testis None None Not available
Other features None Widely spaced nipples (HP:0006610) Generalized hypotonia (HP:0001290) and hyper active behavior (HP:0000752); generalized tonic-clonic seizures Pectus excavatum (HP:0000767), umbilical hernia, right ectopic kidney with no dilatation Truncal hypotonia (HP:0008936) and appendicular hypertonia (HP:0002509) Macrocephaly, high palate, dolichocephaly, vertigo, generalized hypotonia, pectus excavatum, numerous nevi, boggy subcutaneous lesions Web neck, low set wide spaced nipples, shawl scrotum Polyhydramnios, placentamegaly (1100gr), several nevi and cystic scalp formations, Macrocephaly Polyhydramnios, large placenta (800gr), fatigable weakness of skeletal muscles, partial seizures at onset at 13 years with a sharp wave localized in the left temporal region, Macrocephaly History of feeding and swallowing difficulties

Table shows the clinical features of individuals with bi-allelic variants in TMEM94. HPO (human phenotype ontology) terms were specified when available.

“+” and “−” denotes presence and absence of a clinical feature, respectively. ASD, atrial septal defect; VSD, ventricular septal defect; PDA, patent ductus arteriosus;

AVSD, atrioventricular septal defect. ∗cDNA nomenclature based on GenBank NM_001321148.1.