Table 1.
Clinical and molecular characteristics
| Individual | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
|---|---|---|---|---|---|---|---|---|
| TRPM3 variant | ||||||||
| cDNA (NM_020952.4) | c.2509G>A | c.2509G>A | c.2509G>A | c.2509G>A | c.2509G>A | c.2509G>A | c.2509G>A | c.2810C>A |
| Polypeptide (NP_066003.3) | p.(Val837Met) | p.(Val837Met) | p.(Val837Met) | p.(Val837Met) | p.(Val837Met) | p.(Val837Met) | p.(Val837Met) | p.(Pro937Gln) |
| Genomic DNA (NC_000009.11) | g.73213379C>T | g.73213379C>T | g.73213379C>T | g.73213379C>T | g.73213379C>T | g.73213379C>T | g.73213379C>T | g.73168145G>T |
| Zygosity | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous |
| Segregation | De novo | De novo | De novo | De novo | De novo | De novo | De novo | De novo |
| Clinical features | ||||||||
| Gestation (weeks) | 38 | 40 | 42 | 39 | 38 + 3 | 40 | 39 | Term |
| Perinatal history | C/S | N | N | N | N | N | C/S | C/S (repeat) |
| Birth weight (kg) | NR | 3.6 | 3.2 | 3.48 | 3.378 | 3.89 | 3.1 | 2.9 |
| Sex | M | M | F | M | M | M | M | F |
| Age (years) | 16 | 4.75 | 6 | 5.9 | 6.25 | 28 | 38 | 8.1 |
| Height (cm) | 164.5 (Z = −1.0) | 105.1 (Z = −0.7) | 110 (Z = −1.0) | 117 (Z = + 0.3) | 116 (Z = −0.3) | NR | 169.5 (Z = −1.3) | 115.7 (Z = −2.0) |
| Weight (kg) | 73.3 (Z = + 1.0) | 17.6 (Z = −0.1) | 17.8 (Z = −0.9) | 24.5 (Z = + 1.4) | 22 (Z = + 0.3) | NR | 63.2 (Z = −1.0) | 27.8 (Z = + 0.6) |
| BMI (kg/m2) | 27.1 (Z = + 1.8) | 15.9 (Z = + 0.5) | 14.7 (Z = −0.4) | 17.9 (Z = + 1.7) | 16.3 (Z = + 0.7) | NR | 22.1 (Z = −0.0) | 22.3 (Z = + 2.0) |
| OFC (cm) | 55.8 (15 years, 8 months) (Z = + 0.2) | 49.5 (Z = −0.8) | 51 (Z = + 0.2) | 55 (Z = + 2.1) | 53.2 (Z = + 0.7) | 56 (Z = 0) | 57 (Z = + 0.5) | 52 (Z = + 0.2) |
| Developmental delay/intellectual disability | + (Severe) | + (Moderate) | + (Moderate-to-severe) | + (Severe) | + (Severe) | + (Severe) | + (Moderate) | + (Moderate-to-severe) |
| Ambulate independently (age achieved) | + (5 years) | + (With walker) (3 years) | − | + (With walker) | + (4.5 years) | − | + (4 years) | + (3.5 years) |
| Any speech (age attained) | + (5 years) | − | − | − | − | − | + (5 years) | + (2.5 years) |
| Combine words/signs | + | − | − | − | − | − | + (Signs) | + (Sentences) |
| Toilet independently (age attained) | + (9 years) | − | − | − | − | − | NR | (4 years) |
| Autism-like features | + | NR | + | + | + | − | NR | − |
| Electrographically confirmed seizures | + | + | + | + | + | + | Unconfirmed | + |
| Seizure types | Absence | Infantile spasms | GTC | Subclinical, including ESES | NR | Absence and GTC | Absence | Absence |
| Age of first clinical seizure | Absence-like episodes in infancy; first documented EEG abnormalities at 7 years | NR | NR | EEG abnormalities at 3 years | 11 months | 9 months | <1 year | 2 years |
| Current anticonvulsant therapy | Levetiracetam (initial); none (current) | NR | NR | Diazepam qHS (with improvement in ESES) | Levetiracetam | None | Lamotrigine | |
| Age of last clinical seizure | NR (untreated follow-up EEG at age 15 was normal) | NR | NR | NR | 5 years, 9 months | 26 years (EEG remains pathological with diffuse high-amplitude activity) | NR | 6 years |
| Hypotonia | + | + | + | + | + | − | + (mixed tone abnormality) | + |
| Craniofacial gestalt | Nondysmorphic | Nondysmorphic | Nondysmorphic | NR | NR | NR | Distinctive | Nondysmorphic |
| Morphological features | Broad forehead, deeply set eyes, ptosis, bulbous nasal tip, micrognathia, prominent lobule of ear, tapering fingers | Short philtrum, long nose, turricephaly | NR | Broad forehead, deeply set eyes, flat midface, short philtrum, micrognathia, broad halluces, fifth-finger clinodactyly, pectus excavatum | Broad forehead, low nasal bridge, unilateral preauricular pit, short broad thumbs | Micrognathia, high palate | Mild facial asymmetry, ptosis, telecanthus, bulbous nasal tip, micrognathia, short neck, low hairline | Broad forehead, deeply set eyes, upslanting palpebral fissures, bulbous/upturned nasal tip, short philtrum, large oral aperture, facial capillary hemangioma |
| Other clinical features | C1 spinal stenosis; Chiari I malformation; scoliosis; torticollis; plagiocephaly; thickened filum terminale; bilateral talipes equinovarus; strabismus (exotropia OU) | EMG/NCS normal | − | Strabismus | Cryptorchidism, micropenis, bilateral talipes equinovarus | Neonatal hypoglycemia; unilateral hip dysplasia; scoliosis | Atlanto-occipital fusion, strabismus (exotropia), hands held ‘fisted’ until 9 months, athetoid movements in infancy, pes planus | Choreoathetoid movements in infancy (age 5 months), strabismus, scoliosis |
| Brain MRI | Possible mild cerebral volume loss | Normal | Normal | Normal | Ventriculomegaly, nonspecific periventricular white matter hyperintensities | Normal | Normal | Normal |
| Apparent heat or pain insensitivity | + (Heat) | NR | NR | NR | + (Pain) | − | NR | NR |
| Genetic investigations | ||||||||
| aCGH | Normal | Normal | Normal | Normal | Normal | Normal | Normal | Normal |
| Fragile X | Normal | Normal | Normal | Normal | N/A | Normal | Normal | N/A |
| Other (nondiagnostic) genetic investigations | ID panel (170 genes), PHF6 | NR | MECP2, SMA | NR | NR | NR | 9 gene XLID panel, MCT8 | mtDNA, POLG, DGUOK, TK2, SUCLA2, ID panel (196 genes) |
aCGH microarray-based comparative genomic hybridization, DOL day of life, EMG electromyograph, ESES electrographic status epilepticus of sleep, GTC generalized tonic-clonic, ID intellectual disability, N normal, N/A not applicable, NCS nerve conduction study, NR not recorded, OFC occipitofrontal circumference, OU oculus uterque (“of both eyes”), qHS quaque hora somni (“nightly”), SMA spinal muscular atrophy, VUS variant of unclear clinical significance, XLID x-linked intellectual disability