Table 1 Clinical and molecular data of individuals with bi-allelic variants in CELSR3

From: Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

 

Individual

ZYG

Variant

MAF

CADD;

P; S; M

ID / DD

Tonus

Seizures

Brain, NTD

OFC

CAKUT

Other

CNS

1: II-1

CH

c.1574G>A, p.(Arg525His)

2.31e-5

27.5;

3; D; T

DD

np

np

np

-2.21 z

np

Atopic dermatitis, frequent febrile infections

c.9299G>C, p.(Gly3100Ala)

NR

24.8;

2; D; HT

2: II-1

CH

c.7423C>T, p.(Arg2475Trp)

6.57e-5

28.1;

3; D; N

ID, DD

Central hypotonia

BNS seizures, DEE

np

np

np

Neonatal hypoglycaemia, TTTS (acceptor), FTT, facial dysmorphism

c.8758C>T, p.(Arg2920Trp)

1.97e-5

25.7;

1; D; HT

2: II-2

CH

c.7423C>T, p.(Arg2475Trp)

6.57e-5

28.1;

3; D; N

ID, DD

Central hypotonia

BNS seizures, DEE

Delayed opercularisation

np

np

Neonatal hypoglycaemia, TTTS (donor), FTT, facial dysmorphism

c.8758C>T, p.(Arg2920Trp)

1.97e-5

25.7;

1; D; HT

3: II-1

Hom

c.6304G>A, p.(Ala2102Thr)

NR

24.1;

1; D; SI

Global DD

Hypotonia

LGS

Prominence of subarachnoid spaces

np

X

Strabismus, sleep disturbance

4: II-3

CH

c.5059C>T, p.(His1687Tyr)

1.97e-5

23.6;

1; D; SI

ID

Hypotonia

Seizures

Pachygyria, double cortex

np

X

X

c.7075C>T, p.(Pro2359Ser)

1.98e-5

23.3;

2; T; SI

5: II-2

CH

c.7224_7226del, (p.Ile2409del)

1.32e-5

25.3;

NR; NR; I

PSM-R

np

np

X

np

X

Autoaggressivity, autism-spectrum-disorder, stereotypies, pectus excavatum, facial dysmorphism

c.8480C>A, (p.Thr2827Asn)

NR

17.8;

3; D; T

6: II-1

Hom

c.7999G>A, p.(Gly2667Ser)

NR

26.5;

3; D; I

ID, DD

np

np

Hairy naevus lumbal

np

np

Obesity, facial dysmorphism, stereotypies, sleep disturbance

CNS+CAKUT

7: II-1

Hom

c.6959T>C, p.(Val2320Ala)

NR

27.2;

3; D; SI

np

np

np

Polymicrogyria, subependymal heterotopia

np

MCDK, contralateral compensatory hypertrophy

X

8: II-1

Hom

c.4034C>T, p.(Pro1345Leu)

2.63e-5

22.8;

1; T; SI

DD

Hypotonia and joint laxity

Generalized seizures

Obstructive hydrocephalus, ACC, cerebral hypoplasia

+2.31 z

Unilateral ectopic kidney

Rib deformities, ASD, sensorineural hearing loss, growth retardation, facial dysmorphism

9: II-1

CH

c.3712C>T, p.(Arg1238Cys)

6.57e-6

28.2;

3; D; I

ID, DD

Asymmetric motor exam

Complex febrile seizures

Chiari I, L, periventricular cysts, fatty filum / TCS

+1.55 z

Duplicated collecting system, irregular bladder wall

Anxiety, facial dysmorphism

c.7501G>A, p.(Glu2501Lys)

3.94e-5

25;

3; D; I

CAKUT

10: II-1

Hom

c.3142C>T, p.(Arg1048Trp)

3.29e-5

23;

3; D; SI

np

np

np

X

np

Bilateral VUR, duplicated collecting system

X

11: II-1

Hom

c.3100G>C, p.(Glu1034Gln)

7.23e-5

23.3;

2; T; I

np

np

np

X

np

Bilateral UPJO, hydronephrosis, reduced kidney function, diffuse bladder wall thickening

X

  1. Overview of clinical and molecular data of twelve individuals from eleven independent families with bi-allelic variants in CELSR3. Further details, as well as information on three families which are not included in the main text, can be found in Supplement A and B.
  2. CNS central nervous system, CAKUT congenital anomalies of the kidneys and urinary tract, ZYG zygosity, CH compound heterozygous, Hom homozygous, MAF minor allele frequency in gnomAD v3.1, NR not reported, P PolyPhen-2 (1 benign, 2 possibly damaging, 3 probably damaging), S SIFT (T tolerated, D deleterious), M MetaDome (HT highly tolerant, T tolerant, N neutral, SI slightly intolerant, I intolerant), ID intellectual disability, DD developmental delay, PSM-R psychomotor regression, BNS Blitz-Nick-Salaam, DEE developmental and epileptic encephalopathy, LGS Lennox-Gastaut syndrome, NTD neural tube defect, ACC agenesis of corpus callosum, L leukoencephalopathy, TCS tethered cord syndrome, OFC occipitofrontal circumference, MCDK multicystic dysplastic kidney, VUR vesicoureteral reflux, UPJO ureteropelvic junction obstruction, TTTS twin-to-twin transfusion syndrome, FTT failure to thrive, ASD atrial septal defect, np phenotype not present, X not investigated.
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