Table 1 Clinical features of patients reported here with a dominant KCNH1 or KCNN3 variant.
Patient # | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
Gene | KCNH1 | KCNH1 | KCNH1 | KCNH1 | KCNH1 | KCNN3 | KCNN3 | KCNN3 |
mRNA reference number | NM_172362.2: | NM_172362.2 | NM_172362.2 | NM_172362.2 | NM_172362.2 | NM_002249.6 | NM_002249.6 | NM_002249.6 |
Variant | c.1487G > A p.(Gly496Glu) | c.1070G > A p.(Arg357Gln) | c.1465C > T p.(Leu489Phe) | c.1060A > G p.(Lys354Glu) | c.1486G > A p.(Gly496Arg) | c.1663G > T p.(Val555Phe) | c.1616_1618del p.(Val539del) | c.859G > T p.(Ala287Ser) |
Origin | Parents not tested | de novo | de novo | de novo | Father not tested, not maternal | de novo | de novo | Father not tested, not maternal |
Nationality | Caucasian (British) | Caucasian (Dutch) | Caucasian (USA) | Caucasian (USA) | Caucasian (Dutch) | Caucasian (USA) | Caucasian (British) | Swiss-Indian |
Sex | F | F | M | F | F | M | F | F |
Agea | 39.2 y | 9.75 y | 14 m | 2.95 y | 34 y | 1.25 y | 11.1 y | 30 y |
Birth weight (SD) | 3300 g (40 wks) (−0.4) | 3345 g (40 + 6 wks) (0) | 4320 g (39 wks) (+1.9) | 3373 g (0) | 3870 g (41/42 wks) (+0.8) | 2715 g (33 wks) (+2) | 3430 g (37 wks) (+1) | ND |
Birth length (SD) | ND | 52 cm (−0.1) | 55.9 cm (+2) | 53 cm (+0.8) | 53 cm (+0.3) | 50 cm (+2) | ND | ND |
OFC birth (SD) | 35.2 cm (+0.8) | ND | 35.5 cm (+1) | ND | ND | 36 cm (+3) | 35.2 cm (+1.5) | ND |
Weighta (SD) | 38.0 kg (−2.6) | 25 kg (−1) | 9 kg (−1.8) | 12.5 kg (−0.89) | ND | 9 kg (−2) | 23.3 kg (−0.4) | 89 kg (+1.92) |
Heighta (SD) | 150 cm (−1.7) | 122 cm (−2.5) | 77.5 cm (0) | 94 cm (+0.07) | 174 cm (+0.5) | 75.6 cm (−1) | 124.5 cm (−0.7) | 166.5 cm (+0.5) |
OFCa (SD) | 49.6 cm (−4) | 53.5 cm (+1) | 46 cm (−0.7) | 49.5 cm (+0.32) | 55.8 cm (+0.3) | 49.8 cm (+2.5) | 53.2 cm (+0.9) | 58.5 cm (+3.8) |
DD/ID | Severe DD; unable to walk independently; severe intellectual disability; no speech | Severe DD/ID; supported walking 21 m; autonomous walking 3.5 y; not able to speak words; able to make sounds | Rolling over at 10 m; not sitting; vocalizing, babbling, no words | Motor and speech delay; skills at 4 m level at age 2.8 y | DD; walking independently around 2 y; speech delay, improvement after ear tubes at 2.5 y; moderate ID | DD with sitting independently at 12 m; no spoken words at 15 m | Mild DD; walked at 2.5 y; first words at 18 m; now good speech and language; but requires support in school | DD; walked at 18 m; first words at 2–3 y; special education; mild-to-moderate ID: speaks in sentences, has basic reading skills |
Tonus | Increased tone in limbs with brisk reflexes | Hypotonia; hyperlaxity | Hypotonia | Hypotonia | Hypotonia | Hypotonia | Generalized hypotonia; reflexes difficult to elicit | Mildly increased tone with brisk reflexes |
Seizures | Yes, prenatal onset and after birth; initially myoclonic jerks and later a mixed seizure type; improved but not stopped by medication | Yes, onset at 2.75 y; mixed seizure types (focal and diffuse) and absences | No | Yes (age 4 wks) | Yes, onset shortly after birth with generalized tonic-clonic seizures; several times status epilepticus after stopping medication or inadequate doses | No | No | Unclear (see section “Other anomalies”) |
EEG | Abnormal | Abnormal | ND | Abnormal | Multifocal abnormalities | ND | Normal | Normal |
MRI scan | Microcephaly, mild cerebral atrophy, mild cerebellar hypoplasia (15.2 y) | Somewhat prominent perivascular spaces and high collateral sulcus, further normal | Normal | Normal | ND | Enlarged extra-axial fluid spaces | Normal | Agenesis of corpus callosum |
Hearing | Normal | Normal | Passed newborn hearing screen; mild/moderate HL with effusion requiring PE tubes | Normal | Normal | Normal | Normal | Normal |
Eye findings | Visual inattention in infancy, gradually improved; left convergent squint | Normal | Normal structural eye exam; severe cortical visual impairment | No evaluation | Normal vision, no evaluation | Normal | Normal | Strabismus |
Craniofacial dysmorphism | Narrow face; upslanted palpebral fissures; prominent chin; tented upper lip vermilion; highly arched palate | Hypotonic facies; prominent forehead with bitemporal narrowing; mild eversion of lateral part lower eyelids; protruding maxilla and mandible; wide mouth; full lips; open mouth; tongue protrusion | Hypotonic facies; long face; large jowls; micrognathia and high palate (Pierre–Robin without cleft); arched eyebrows; very long eyelashes; epicanthal folds; appearance of widened inner canthal distance; flat nasal bridge; short upturned nose; tented upper lip | Coarse face; epicanthal folds; slightly broad nasal tip | At adult age: long and narrow face; full hair; hollow cheeks; downslanted palpebral fissures; high nasal bridge; large nose; high-arched palate; open mouth appearance; retrognathia; in childhood more round face with full cheeks | Coarse face; synophrys; low nasal bridge; downslanted palpebral fissures; epicanthal folds; long eyelashes; broad nasal tip | Thick hair and eyelashes; low anterior and posterior hair lines; puffy periorbital region; prominent nose with broad tip; depressed nasal bridge; full cheeks and lips; 3 dimples in left cheek | Coarse face; uplifted earlobes; square-shaped helices; low anterior hairline; long eyelashes, high-arched palate; malpositioned teeth; full lower lip |
Gingival enlargement | Yes | Yes | Marked (maxilla) | Yes, at age 2 y | Yes | Marked (surgical reduction) | Yes | No |
Skeletal abnormalities of hands and feet | Long and thin hands; proximal placement of thumbs; long narrow feet; long toes with overriding of 2nd toes over 3rd | Hands: slight tapering of fingers; broad thumbs; short distal phalanges of fingers. Feet: broad halluces | Proximally placed and hypoplastic thumbs; tapering of second toe | No signs of skeletal anomaly on hands (radiographs) and feet | Short distal phalanges; hypermobile thumbs; wide forefoot; mild hallux valgus | Distal digital hypoplasia; long great toes | Slight shortening of fingers distally; tapering of 5th fingers; toes unremarkable | Broad big toes; distal phalanges of the toes appear foreshortened |
Aplastic or hypoplastic nails | Nails present, but hypoplastic and concave on the fingers | Hands: small nails/slight hypoplasia of nails. Feet: small nails/slight hypoplasia of nails of toes 1 and 5 | Anonychia of toes 1 and 2 and hypoplastic nails on toes 3–5; hypoplastic and dysplastic thumb nails | Elongated toes with hypoplastic nails, especially on the 5th toes | Hypoplastic nails | Hands: aplastic nails of thumbs; extreme nail hypoplasia of fingers 2–5. Feet: nail aplasia of all toes | Small nails, which are concave and grow slowly | Hypoplastic nails |
Scoliosis | Yes, severe | No | No | Moderate thoracolumbar scoliosis; increased thoracolumbar kyphosis | Mild | ND | No | No |
Hypertrichosis | Normal scalp hair and no generalized hypertrichosis | Thick scalp hair; high anterior hairline; long eyelashes | Very long eyelashes | None | Thick scalp hair; hairy legs but no generalized hypertrichosis | Synophrys | Thick scalp hair, but minimal on trunk and extensor surfaces of limbs | Hypertrichosis on face and trunk; low anterior hairline |
Liver findings | Liver function normal | Slightly elevated ASAT (84 U/L) and ALAT (98 U/L) at 8.8 y; abdominal ultrasound normal at 3 y | ND | ND | ND | ND | Liver function normal | Liver enzymes normal |
Other anomalies | Made some developmental progress until 5 y of age, after which, skills were lost; persistent movement disorder with myoclonic jerks, exacerbated by discomfort or fever | Sialorrhea (required surgery); recurrent ear infections; hip dysplasia; constipation; sleep problems (nitrazepam treatment); behavior problems: can be aggressive and can harm herself by pulling out her hairs; features of autism | Moderate tracheomalacia | None | Bipolar disorder (with a psychotic episode) treated with antipsychotic medication; right bundle branch block; right axis deviation; in childhood ataxia and tremor | Polyhydramnios; hypospadias; microcolon; progressive left ventricular dilatation; mild coronary artery dilation | Soft velvety skin with normal skin creases | Inspiratory stridor in infancy; episodes of recurrent vomiting and lowered vigilance compatible with insular epilepsy (not confirmed); antipsychotic medications for possible hallucinations |
