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Table 1 Overlapping phenotypes in the CACNA1E patients

From: De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures

  Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7
Genetics
CACNA1E variant (NM_000721.4)
Coordinates in hg19
c.488T>C (p.Met163Thr)
1:181480622T>C
c.1499A>G
(p.Gln500Arg)
1:181686412 A>G
c.2060C>T (p.Thr687Ile)
1:181690997 C>T
c.2104G>T (p.Ala702Ser)
1:181693635 G>T
c.2105C>T (p.Ala702Val)
1:181693636 C>T
c.2108T>G (p.Val703Gly)
1: 181693639T>G
c.3422+1G>A (p.?)
1:181705571 G>A
Inheritance de novo de novo de novo de novo de novo de novo de novo
Localization S3 of Domain I Intersegment S1–S2 of Domain II S6 of Domain II S6 of Domain II S6 of Domain II S6 of Domain II Beginning of Domain III
Age at genetics assessment 6 yo 8 yo 18 mo 31 yo 6 yo 4 yo 7 mo 6 yo 6 mo
Clinical characteristics and history
Sex M M M F M F M
Age at onset symptoms/parental concern 14 mo (regression) 8–10 mo 12 mo 6 mo Shortly after birth Neonatal GI symptoms related to sucrose isomaltase deficiency; DD at 6 mo 24 mo (regression)
Age at last clinical evaluation 7 yo 10 mo 25 mo 31 yo 6 yo 4 yo 8.5 yo
Seizures No No No IS at 6.5 mo—ACTH No No No
EEG (age) Left parieto sagittal discharges (6 yo) activated during sleep Unremarkable (8 yo) NA NA Multifocal spike and slow wave discharges (4.5 yo); bifrontal sharps activated during sleep NA NA
Neurological evaluation
Head circumference at last evaluation (Percentile) 52 cm (P10–25) 51.4 cm (P25–50) 47.6 cm (P10–25) 55 cm (P25–50) 52 cm (P25–50) 48.8 cm (P3–10) 52 cm (P10–25)
Developmental regression number (age) 2 (14 mo, 5 yo)
Loss of communication skills, autonomy and diurnal bladder control at 5 yo
1 (4 yo)
Fine and global motor skills regression
1 (12–18 mo)
Language regression
No NA No 1 (24 mo)
Language regression
GDD* + + + + + + +
Intellectual disabilities (> 5yo)** Moderate Moderate to severe NA Severe NA NA Severe
Language development Delayed
Verbal, able to express complete sentences
Delayed
Speaks few words at 8 yo
Delayed
No words at 2 yo
Delayed
Some single-words
Delayed
Non-verbal
Delayed
Babbles at 4 yo
Delayed
Phrase speech at 48 mo; echolalia
Social behavior/impairment Abnormal/ASD diagnosis Abnormal/ ASD diagnosis None reported at 2 yo Abnormal NA Social: makes eye contact, smiles, giggles Abnormal/ASD diagnosis
Sensory issues Produces loud sounds
No reaction to pain
Sensory seeking behavior (repetitive tapping) Reduced pain sensitivity Displayed sensory-seeking behaviors Picky eater
Sensitive to noise and touch
Motor stereotypies Body rocking, hand flapping Hand flapping NA Hand flapping, hand stereotypies NA None Persistent motor stereotypies
Tone disorder Hypotonia Hypotonia Hypotonia None Hypotonia Hypotonia None
Motor development Delayed
Ambulatory
Delayed
Ambulatory
Delayed,
Not walking at 2 yo
Delayed
Ambulatory
Delayed
Not walking, sat at 2.5 yo
Delayed
Not walking at 4 yo
Apraxia
Delayed
Ambulatory
  1. ACTH adrenocorticotropic hormone, DD developmental delay, F female, GI gastrointestinal, IS infantile spasm, M male, mo months old, NA not available, S segment, yo year old. *No developmental quotient was available; **For patient 1 a WIPPSI IV was performed; the type of testing used for the IQ assessment was not available for the other patients