Table 1 Clinical features in study subjects and previous publications.
Family ID | Subject ID | Gender | UBA2 variant, transcript | Current age or age at exam (years) | Developmental delay/neurodevelopmental details | Height percentile (most recent or at stated age) | Weight percentile (most recent or at stated age) | Head circumference percentile (most recent/stated age) | Early growth problems | Craniofacial features | Aplasia cutis congenita | Other ectodermal variations | Ectrodactyly/oligodactyly | Other skeletal anomalies | Other anomalies/features: cardiac, renal, genital, ocular, miscellaneous | Other genetic/chromosomal results |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | III-2 | F | c.816_817delAT: p.Trp273Alafs*13 NM_005499 | 37 | Normal development, but had behavior problems as child, history of seizures, mini strokes | <5 | Increased | 2 | Tall forehead/high hairline, hypertelorism, broad nasal root, facial asymmetry, cleft chin, ptosis, simple low-set ears | No | Peg teeth, yellow teeth, thin hair, xerosis | No | Hypoplastic distal flexion creases, clinodactyly, syndactyly, camptodactyly, hip abnormality | Atrial fibrillation, mitral regurgitation by history but recent echo was normal; hydronephrosis; wears glasses; focal nodular hyperplasia of the liver, hypofibrinogenemia | Heterozygous for FGG LPATH variant: D344N; WNT10B heterozygous VUS: I285T | |
1 | IV-1 | F | c.816_817delAT: p.Trp273Alafs*13 maternal NM_005499 | 15 | Mild delays, hypotonia, has individualized educational plan, but she is academically on target | 25 | 67 | 2 | Yes | Tall forehead/high hairline, downslanted palpebral fissures, hypertelorism, broad nasal root, facial asymmetry, gap between incisors, slightly bifid uvula | No | Natal tooth, peg teeth, thin hair, eczema, keratosis pilaris, dental problems | No | Hypoplastic distal flexion creases, clinodactyly, syndactyly, camptodactyly, hip abnormality, scoliosis, pectus excavatum | ASD, aberrant right subclavian; hydronephrosis/pelviectasis, GU reflux, urinary tract infections; high myopia; hypofibrinogenemia | FGG heterozygous LPATH variant: p.D344N; microarray: dup22q11.2 |
1 | IV-2 | M | c.816_817delAT: p.Trp273Alafs*13 maternal NM_005499 | 13 | Autism spectrum disorder, behavior problems, encopresis, stereotypies, mood swings, hypotonia, normal MRI | 26 | 66 | 20 | Yes | Tall forehead/high hairline, downslanted palpebral fissures, hypertelorism, broad nasal root, facial asymmetry, triangular face, mild synophrys, telecanthus, cleft chin, micrognathia | Yes, single area | Xerosis, thin hair, gaps between teeth, irregular enamel, supernumerary nipple, hyperhidrosis, hyperlinearity of palms, cutis marmorata, nail ridging, keratosis pilaris | No | Clinodactyly, syndactyly, camptodactyly, hip abnormality; wore helmet for torticollis and plagiocephaly | PFO (resolved); astigmatism | Normal CGH; normal MID1 sequencing. |
1 | IV-3 | M | c.816_817delAT: p.Trp273Alafs*13 maternal NM_005499 | 8 | Autism spectrum disorder, hypotonia, possible processing delay, poor coordination, MRI essentially normal | 18 | 54 | ~30 | Yes | Tall forehead/high hairline, orbital asymmetry, square uvula, ankyloglossia, cleft chin | No | Xerosis, keratosis pilaris, unruly hair, atopic dermatitis, history of heat exhaustion | No | Clinodactyly, syndactyly, camptodactyly, hip abnormality, wormian bones, mild pectus excavatum | PFO (resolved); astigmatism; hypofibrinogenemia | FGG heterozygous LPATH variant: p.D344N |
1 | IV-4 | F | c.816_817delAT: p.Trp273Alafs*13 maternal NM_005499 | 7 | Mild delays, intermittent intention tremor, brisk patellar reflexes, poor balance, hypotonia, normal cognitive skills, MRI normal | 11 | 11 | ~2 | Yes | Tall forehead/high hairline, downslanted palpebral fissures, broad nasal root, facial asymmetry, low-set ears, simple cartilage, wide uvula, cleft chin, micrognathia | Yes, multiple areas | Xerosis, mild ichthyosis, keratoderma follicular prominence, thin dry hair, frayed toenails, hyperlinear palms, hypohidrosis | Yes, unilateral hand | Hypoplastic distal flexion creases, brachydactyly of toes, clinodactyly, syndactyly, camptodactyly, hip abnormality, mild pectus excavatum and hyperextensibility, wormian bones | PFO (resolved); early myopia, −4 diopters, improved; history of “twisted optic nerves”; hypofibrinogenemia; reduced IgA, IgM | Normal SNP microarray; normal TP63 gene sequencing; FGG heterozygous LPATH variant: p.D344N; WNT10B heterozygous VUS: p.I285T. |
2 | II-1 | M | c.1376_1377insT: p.Thr460Aspfs*24 de novo NM_005499.2 | 21 | Delays; hypotonia, sensory integration problems, normal cognitive development | 10 | <3 | ~5 | No | Tall forehead/high hairline, downslanted palpebral fissures, broad nasal root, facial asymmetry, epicanthal folds, long and smooth philtrum, high arched palate, dental crowding | No | No | No | Long thin fingers, foot anomalies, clinodactyly, pectus excavatum, plagiocephaly | Cryptorchidism, hydrocele | |
2 | II-2 | M | c.1376_1377insT: p.Thr460Aspfs*24 de novo NM_005499.2 | 12 | Delayed motor skills, hypotonia, sensory integration problems | “Low” | <5 | Yes | Downslanted palpebral fissures, broad nasal root, zygomatic arch hypoplasia, simple, low-set posteriorly rotated ears, preauricular tag, long smooth philtrum, high arched palate, micrognathia | No | No | No | Dysplastic metatarsals, toes point outward, kyphoscoliosis | Hypospadias, inguinal hernia | ||
2 | II-3 | M | c.1376_1377insT: p.Thr460Aspfs*24 de novo NM_005499.2 | 6 | Delays, unstable gait, poor fine motor skills, sensory integration problems, poor balance, hypotonia, normal cognitive skills | <3 | <3 | <3 | Yes | Normally set ears | Not noted | No | Yes, unilateral partial central cleft of hand, polydactyly of third finger | Syndactyly, camptodactyly | Cryptorchidism, hydrocele | 46, XY and normal microarray |
3 | I-2 | M | c.364C>T: p.Arg122* NM_005499 | 45 | Delays, learning difficulties in school, depression in adulthood | <5 | >95 | ~5–10 | Tall forehead/high hairline, hypertelorism, broad nasal root, low-set prominent ears, thin vermilion border, mild micrognathia | Yes, multiple areas | Supernumerary nipples | No | None reported | Recurrent urinary tract infections; asymmetric renal sizes with reduced function of smaller kidney; hypothyroidism, s/p cholecystectomy; inguinal herniorrhaphy; history of pseudotumor cerebri | ||
3 | II-1 | F | c.364C>T: p.Arg122* maternal NM_005499 | 24.5 | Delays (walked at 17 months, first words at 22 months), special education, depression and anxiety as an adult | ~15 | ~93 | <3rd | Tall forehead/high hairline, hypertelorism, broad nasal root, thin upper lip, smooth philtrum, everted lower lip, thick, low-set, and laterally protruding ears, medial eyebrow flare, micrognathia | Yes, 3 areas | Supernumerary nipple | No | None reported | Bicuspid aortic valve; astigmatism; s/p cholecystectomy; migraines; low back pain | ||
3 | II-2 | M | c.364C>T: p.Arg122* maternal NM_005499 | 21.5 | Delays recognized at 16 months, learning difficulties and special education, bipolar disease, panic attacks and social phobias as an adult | ~20 | ~15 | ~60–70 | Tall forehead/high hairline, downslanted palpebral fissures, hypertelorism, broad nasal root, prominent columella, bulbous tip of the nose, micrognathia | Yes, single area | Supernumerary nipple | No | None reported | Cryptorchidism, astigmatism, asthma | ||
3 | III-1 | F | c.364C>T: p.Arg122* maternal NM_005499 | 2.75 | Delays (at 16 months, cognitive function was at the 8 month old level, motor skills were at the 9 month level; at 30 months: still no sentences) | 50 | 75–90 | 3–10 | No | Tall forehead/high hairline, downslanted palpebral fissures, hypertelorism, broad nasal root, low-set ears, micrognathia | Yes, multiple areas | Supernumerary nipple | No | None reported | Frequent otitis, constipation | |
4 | II-1 | F | c.167A>C: p.Asn56Thr de novo NM_005499.2 | 21 | Delayed motor skills, attention deficit disorder, sat independently at 12 months, walked at 22 months, first word at 18 months, sentences after 2 years | <3 | <3 | <3 | Yes | High hairline, broad forehead, hypertelorism, broad nasal root, delayed dentition, mild facial dysmorphism | Yes | Thin, sparse hair, coarse skin, poor sweating, cries with tears | No | Clinodactyly, overlapping toes on right foot (3,4), delayed bone age, kyphoscoliosis treated with bracing | Renal hypoplasia, chronic kidney disease, stable; bilateral optic nerve hypoplasia with normal vision; postural orthostatic hypotension; hypothyroidism, growth hormone treatment, headaches, no breast development (budding only), menarche at 14 years, pubic hair, no axillary hair | BAZ1B:heterozygous VUS, de novo fs c.3317delA; SOS1: heterozygous variant c.281T>C; COX1: homoplasmic p.I97V; NRXN1: heterozygous VUS, p.G744R (maternal) |
5 | II-1 | F | c.1447G>A: p.Glu483Lys de novo NM_005499.2 | 4.75 | Global delay (gross motor and speech), nonverbal, refractory seizures, infantile spasms, hyperactivity, hypotonia | ~75 | ~10 | ~25 | No | Epicanthal folds | Yes | Normal hair and nails | Pes planus | Hemangiomas (left ear, back); anteriorly placed anus | Normal microarray, normal Prader– Willi/Angelman methylation, epilepsy panel: heterozygous VUS in GABRB3, paternal: p.R409Q | |
6 | II-1 | M | c.800T>A: p.Leu267* de novo NM_005499.2 | 1.5 | Normal development | 10–25 | 10–25 | 5–10 | No | Tall forehead/high hairline, hypertelorism, epicanthal folds, pseudostrabismus | No | Yes, bilateral ectrodactyly of the feet | Clinodactyly, complete bilateral 2–3 finger syndactyly camptodactyly | Cryptorchidism; bilateral inguinal hernias. | Normal SNP microarray | |
7 | II-1 | M | c.364C>G: p.Arg122Gly de novo NM_005499.2 | 3.9 | Gross, fine motor and speech delays, persistent | 75–90 | ~75 | 25 | No | Tall forehead/high hairline, broad nasal root, left preauricular ear tag, narrow palate, vertical cleft/groove in chin | No | Diffuse patches of hypopigmentation | 4 limb ectrodactyly, oligodactyly of both feet | Syndactyly as part of ectrodactyly | VSD, not clinically significant | Normal prenatal microarray; normal ES at another clinical lab |
Marble et al. 201718 | F | c.71G>T: p.Gly24Val de novo NM_005499 | 2.5 | Delayed motor development, normal cognitive ability | 25–50 | 3rd | 25–50 | Yes | Tall forehead/high hairline, downslanted palpebral fissures, suspected hypertelorism and broad nasal root | Yes, single large area | Thin hair in photos | No | Clinodactyly, hip abnormality | Duane anomaly, strabismus; recurrent otitis media, croup, tonsillitis | ||
Yamoto et al. 201919 | II-1 | M | c.1324dupT: p.Tyr442Leufs*17 de novo NM_005499.2 | Bilateral ectrodactyly, oligodactyly, hands and feet | Clinodactyly, long bone deficiency of tibias | Undermasculinized external genitalia | ||||||||||
Wang et al. 201921 | M | c.327delT: p.Phe109Leufs*3 maternal NM_005499.3 | 4 | Normal development | 10–25 (birth) | <3 (birth) | <10 (birth) | Yes, two areas | Bilateral ectrodactyly, oligodactyly | Syndactyly as part of ectrodactyly, low lying conus medullaris | Horseshoe kidney, tracheoesophageal fistula | Normal karyotype, microarray | ||||
Wang et al. 201921 | F | c.327delT: p.Phe109Leufs*3 NM_005499.3 | 35 | Normal development | Yes | No | None reported | |||||||||
Aerden et al. 202020 | M | c.612delA: p.Glu205Lysfs*63 de novo NM_005499.2 | 8 | Speech delay, normal motor milestones, learning difficulties, autism diagnosed at 8 years, intelligence quotient 76 | ~25–50 (3.6 years) | ~25 (3.6 years) | ~20 (3.6 years) | Yes | Retrognathia, low-set and prominent ears, fullness of upper eyelids | Supernumerary nipple, increased hair on back, dry, sparse scalp hair | Yes | Polydactyly with six metatarsals on right foot, multiple bony anomalies in feet, syndactyly of toes, normal hands, transient hip instability; normal hands | Strabismus, hypermetropia |
