Table 1.
Clinical and genetic findings of individuals with variants in CLCN3
| Individual # | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10.1 | 10.2 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| CLCN3 variant information | |||||||||||
| Genomic (GRCh38) | chr4: 169680143-A-G | chr4: 169692139-T-C | chr4: 169695646 T>C | chr4: 169697409-C-T | chr4: 169697528-A-C | chr4: 169704143-C-T | chr4: 169704143-C-T | chr4: 169706937-T-C | chr4: 169713244-T-C | chr4: 169687675_169687678del | chr4: 169687675_169687678del |
| cDNA (NM_173872.3) | c.254A>G | c.755T>C | c.971T>C | c.1238C>T | c.1357A>C | c.1709C>T | c.1709C>T | c.1820T>C | c.2315T>C | c.336_339del | c.336_339del |
| Protein | p.Tyr85Cys | p.Ile252Thr | p.Val324Ala | p.Ala413Val | p.Ser453Arg | p.Thr570Ile | p.Thr570Ile | p.Ile607Thr | p.Val772Ala | p.Lys112Asnfs∗6 | p.Lys112Asnfs∗6 |
| Inheritance | de novo | de novo | de novo | unknown (adopted) | de novo | de novo | de novo | de novo | de novo | homozygous (parents unaffected) | homozygous (parents unaffected) |
| Sequencing method | trio WES, clinical | trio WES, clinical | WES, research | singleton WES, clinical | trio WES, clinical | trio WGS, research | trio WES, research | trio WES, clinical | trio WES, clinical | trio WES, research | trio WES, research |
| CADD score | 28.7 | 26.2 | 27.4 | 22.3 | 26.7 | 23.6 | 23.6 | 27.1 | 23.4 | 32 | 32 |
| Patient information | |||||||||||
| Sex | female | male | male | female | female | female | female | female | male | male | male |
| Ethnicity | Turkish (consanguineous) | European | European | European | Metis/European | European | Ashkenazi Jewish | European | Uruguayan | European | European |
| Institution | Erasmus University Medical Center | Bambino Gesù Children’s Hospital | University of California San Francisco | Emory University School of Medicine | University of British Columbia | Broad Institute of MIT and Harvard | University of British Columbia | University Medical Center Hamburg-Eppendorf | Boston Children’s Hospital | University Hospital of Düsseldorf | University Hospital of Düsseldorf |
| Age | 16 y | 5 y | 17 y | 10 y | 5 y | 13 y | 12 y | 23 d (deceased) | 7 y | 18 m | 14 m (deceased) |
| Gestational age | 40 weeks | 39 weeks | 39 3/7 weeks | ND | 41 3/7 weeks | 41 2/7 weeks | approx. 40 weeks | 39 6/7 weeks | approx. 39 weeks | 40 weeks | 40 weeks |
| Birth weight | 4,000 g (+1.57 SD, 94th %ile) | 3,340 g (−0.35 SD) | 3,020 g (−0.89 SD, 19th %ile) | ND | 3,960 g (>+1.19 SD, >88.3%ile) | 2,790 g (−1.01 SD, 16th %ile) | 3,203 g (−0.06 SD, 47th %ile) | 3,130 g (−0.8 SD) | 2,485 g (−3.94 SD, 3rd %ile) | 3,230 g (25th %ile) | 3,660 g (50th %ile) |
| Birth length | ND | 52 cm (+0.70 SD) | 50 cm (−0.22 SD, 41%ile) | ND | 54 cm (+2.17 SD, 98.5%ile) | 52 cm (+1.59 SD, 94th %ile) | 49 cm (−0.08 SD, 47th %ile) | 50.8 cm (−0.4 SD) | 44 cm (−3.11 SD, 0%ile) | 53 cm (50th %ile) | 55 cm (90–97th %ile) |
| OFC Birth | ND | 34.5 cm (−0.61 SD) | 33 cm (−1.16 SD, 12th %ile) | ND | 35 cm (+0.42 SD, 66.4%ile) | 32 cm (−1.59 SD, 6th %ile) | 33.5 cm (−0.32 SD, 37th %ile) | 40.5 cm (+4.5 SD) | ND | 34 cm (10th %ile) | 34.5 cm (10–25th %ile) |
| Failure to thrive | N | N | Y | N | N | Y | N | Y | Y | N | N |
| Feeding issues | Y | Y | Y | Y | Y | Y | N | Y | Y | N | Y |
| Neurological features | |||||||||||
| Speech development | delayed | absent | absent | delayed | delayed | delayed with regression at 3 y | delayed | N/A | absent | absent | absent |
| Gross motor development | delayed, walks independently | delayed, walks independently (starting a 6 y) | delayed, does not walk independently | delayed, walks independently | delayed, walks independently with difficulty and AFOs | delayed, walks independently | delayed, walks independently | N/A | delayed, sits supported, cannot crawl or walk | delayed, does not walk independently | delayed, never walked independently |
| Fine motor development | delayed | delayed | delayed | delayed | delayed | delayed | delayed | N/A | delayed | delayed | delayed |
| Developmental delay/intellectual disability | mild-moderate ID (IQ 55) | severe ID (QS 24) | severe ID | mild ID (IQ 71) | GDD | profound ID | mild-moderate ID | N/A | severe ID | GDD | GDD |
| Seizures | N | tonic clonic, onset 29 m | myoclonic, onset 4 y, controlled by clobazam + oxcarbazepine | N | non-clinical seizures | N | N | N | seizures, onset 6 m, well controlled w/ Keppra | focal seizure onset in neonatal period; start at 3 months multifocal tonic and myoclonic seizures | seizure onset 3 months, tonic and myoclonic |
| Autism | Y | not evaluated | N | Y | N | Y | N | N/A | N | N | Y |
| Hypotonia | N | severe | moderate | mild | moderate | mild | moderate | N | truncal and nuchal | N | N, has severe spasticity |
| Mood or behavioral abnormalities | temper tantrums since puberty | N | N | hyperactive, OCD, anxiety, stereotypies | self- stimulatory actions when younger | severe anxiety, self-injurious, intermittent explosive behavior | severe anxiety | N/A | N | severe restlessness | N |
| Other Clinical Findings | |||||||||||
| Vision/Eye abnormalities | N | unilateral strabismus | bilateral partial optic atrophy, retinal dystrophy, nystagmus | strabismus | strabismus, intermittent right exotropia | strabismus, hyperopia | anisometropia | N/A | esotropia | salt and pepper fundus pigmentation, nystagmus, no fixation | salt and pepper fundus pigmentation, nystagmus, no fixation |
| Hearing impairment | N | N | N | unilateral hearing impairment due to hx of cholesteatoma | N | mild sensorineural hearing loss | N | N/A | N | N | N |
| Dysmorphic features | Y | Y | N | Y | Y | Y | Y | Y | Y | Y | Y |
| Congenital anomalies | N | N | crytorchdism | possible hydrocephalus at birth | N | N | N | arthrogryposis multiplex congenita, hip dislocation | ASD, BL talipes equinovarus, BL renal pyelectasis, BL hand contractures, congenital radial head dislocation, hypoplastic/absent coccyx | N | N |
Y, present; N, absent; ND, no data; N/A, not applicable; GDD, global developmental delay; BL, bilateral.