Table 3 Open in new tab CALM cases with...

Gene

Variant

Domain

Cardiological phenotype

Neurodevelopmental/neurological features

Structural abnormalities

Congenital heart diseases

CALM1

p.N98S (p.Asn98Ser)

EF-hand III, Ca²⁺-chelation loop

LQTS/CPVT

Autism

CALM1

p.N98S (p.Asn98Ser)

EF-hand III, Ca²⁺-chelation loop

CPVT

Mild intellectual disability, ADHD, epilepsy

CALM1

p.E105A (p.Glu105Ala)

EF-hand III, Ca²⁺-chelation loop

LQTS/CPVT

Developmental disorder with hyperactivity

CALM1

p.E105K (p.Glu105Lys)

EF-hand III, Ca²⁺-chelation loop

Atypical

Developmental delay, recurrent seizures (benign focal seizure susceptibility syndrome)

CALM1

p.D132V (p.Asp132Val)

EF-hand IV, Ca²⁺-chelating

LQTS

Autism, ADHD, language disorder, amblyopia

CALM1

p.E141V (p.Glu141Val)

EF-hand IV, Ca²⁺-chelation loop

LQTS

ADHD, dyslexia

Mildly impaired LV diastolic function, mild LA dilatation

CALM1

p.F142L (p.Phe142Leu)

EF-hand IV

LQTS

Autism, intellectual disability

Non-compaction cardiomyopathy

CALM1

p.F142L (p.Phe142Leu)

EF-hand IV

LQTS

Epilepsy, infantile spasms, EEG dysrhythmia

PFO, small aortopulmonary collateral from the distal arch

CALM1

p.F142L (p.Phe142Leu)

EF-hand IV

LQTS

Autism, intellectual disability, developmental delay, epilepsy, arachnoid cyst fenestration

ASD, ostium secundum

CALM2

p.T35I (p.Thr35Ile)

EF hand I

CPVT

Social communication disorder, gender dysphoria

CALM2

p.E46K (p.Glu46Lys)

EF hand II

CPVT

Autism, epilepsy with abnormal EEG

PDA

CALM2

p.E46K (p.Glu46Lys)

EF hand II

CPVT

Autism, severe intellectual disability

PDA

CALM2

p.T63R (p.Thr63Arg)

EF-hand II, Ca²⁺-chelation loop

Seizures

Dilated cardiac cavities at autopsy

CALM2

p.I64M (p.Ile64Met)

EF-hand II, Ca²⁺-chelation loop

Absent

Malformation-neurodevelopmental disorder syndrome: jejunal membranous atresia, neurodevelopmental disorder, generalized joint laxity, some dysmorphic features

CALM2

p.N98I

EF-hand III, Ca²⁺-chelation loop

LQTS

ADHD, dyslexia, dyspraxia

Concentric LV hypertrophy

CALM2

p.N138K (p.Asn138Lys)

EF-hand IV, Ca²⁺-chelation loop

LQTS

Mild intellectual disability, ADHD, Rolando focus at EEG

HCM

CALM3

p.D96H (p.Asp96His)

EF-hand III, Ca²⁺-chelation loop

LQTS

Autism, developmental delay

PDA

CALM3

p.N138K (p.Asn138Lys)

EF-hand IV, Ca²⁺-chelation loop

LQTS

Psychiatric disorders

CALM3

p.E141G (p.Glu141Gly)

EF-hand IV, Ca²⁺-chelating

LQTS

Seizures

ASD

CALM3

p.F142L (p.Phe142Leu)

EF-hand IV

LQTS

Autism, developmental delay

RV hypertrophy & dilatation

VSD, aortic overriding

Table 3

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CALM cases with likely primary neurodevelopmental/neurological features and concomitant structural abnormalities and/or congenital heart diseases

Gene	Variant	Domain	Cardiological phenotype	Neurodevelopmental/neurological features	Structural abnormalities	Congenital heart diseases
*CALM1*	p.N98S (p.Asn98Ser)	EF-hand III, Ca²⁺-chelation loop	LQTS/CPVT	Autism	-	-
*CALM1*	p.N98S (p.Asn98Ser)	EF-hand III, Ca²⁺-chelation loop	CPVT	Mild intellectual disability, ADHD, epilepsy	-	-
*CALM1*	p.E105A (p.Glu105Ala)	EF-hand III, Ca²⁺-chelation loop	LQTS/CPVT	Developmental disorder with hyperactivity	-	-
*CALM1*	p.E105K (p.Glu105Lys)	EF-hand III, Ca²⁺-chelation loop	Atypical	Developmental delay, recurrent seizures (benign focal seizure susceptibility syndrome)	-	-
*CALM1*	p.D132V (p.Asp132Val)	EF-hand IV, Ca²⁺-chelating	LQTS	Autism, ADHD, language disorder, amblyopia	-	-
*CALM1*	p.E141V (p.Glu141Val)	EF-hand IV, Ca²⁺-chelation loop	LQTS	ADHD, dyslexia	Mildly impaired LV diastolic function, mild LA dilatation	-
*CALM1*	p.F142L (p.Phe142Leu)	EF-hand IV	LQTS	Autism, intellectual disability	Non-compaction cardiomyopathy	-
*CALM1*	p.F142L (p.Phe142Leu)	EF-hand IV	LQTS	Epilepsy, infantile spasms, EEG dysrhythmia	-	PFO, small aortopulmonary collateral from the distal arch
*CALM1*	p.F142L (p.Phe142Leu)	EF-hand IV	LQTS	Autism, intellectual disability, developmental delay, epilepsy, arachnoid cyst fenestration	-	ASD, ostium secundum
*CALM2*	p.T35I (p.Thr35Ile)	EF hand I	CPVT	Social communication disorder, gender dysphoria	-	-
*CALM2*	p.E46K (p.Glu46Lys)	EF hand II	CPVT	Autism, epilepsy with abnormal EEG	-	PDA
*CALM2*	p.E46K (p.Glu46Lys)	EF hand II	CPVT	Autism, severe intellectual disability	-	PDA
*CALM2*	p.T63R (p.Thr63Arg)	EF-hand II, Ca²⁺-chelation loop	UD	Seizures	Dilated cardiac cavities at autopsy	-
*CALM2*	p.I64M (p.Ile64Met)	EF-hand II, Ca²⁺-chelation loop	Absent	Malformation-neurodevelopmental disorder syndrome: jejunal membranous atresia, neurodevelopmental disorder, generalized joint laxity, some dysmorphic features	-	-
*CALM2*	p.N98I	EF-hand III, Ca²⁺-chelation loop	LQTS	ADHD, dyslexia, dyspraxia	Concentric LV hypertrophy
*CALM2*	p.N138K (p.Asn138Lys)	EF-hand IV, Ca²⁺-chelation loop	LQTS	Mild intellectual disability, ADHD, Rolando focus at EEG	HCM	-
*CALM3*	p.D96H (p.Asp96His)	EF-hand III, Ca²⁺-chelation loop	LQTS	Autism, developmental delay	-	PDA
*CALM3*	p.N138K (p.Asn138Lys)	EF-hand IV, Ca²⁺-chelation loop	LQTS	Psychiatric disorders	-	-
*CALM3*	p.E141G (p.Glu141Gly)	EF-hand IV, Ca²⁺-chelating	LQTS	Seizures	-	ASD
*CALM3*	p.F142L (p.Phe142Leu)	EF-hand IV	LQTS	Autism, developmental delay	RV hypertrophy & dilatation	VSD, aortic overriding

Gene	Variant	Domain	Cardiological phenotype	Neurodevelopmental/neurological features	Structural abnormalities	Congenital heart diseases
*CALM1*	p.N98S (p.Asn98Ser)	EF-hand III, Ca²⁺-chelation loop	LQTS/CPVT	Autism	-	-
*CALM1*	p.N98S (p.Asn98Ser)	EF-hand III, Ca²⁺-chelation loop	CPVT	Mild intellectual disability, ADHD, epilepsy	-	-
*CALM1*	p.E105A (p.Glu105Ala)	EF-hand III, Ca²⁺-chelation loop	LQTS/CPVT	Developmental disorder with hyperactivity	-	-
*CALM1*	p.E105K (p.Glu105Lys)	EF-hand III, Ca²⁺-chelation loop	Atypical	Developmental delay, recurrent seizures (benign focal seizure susceptibility syndrome)	-	-
*CALM1*	p.D132V (p.Asp132Val)	EF-hand IV, Ca²⁺-chelating	LQTS	Autism, ADHD, language disorder, amblyopia	-	-
*CALM1*	p.E141V (p.Glu141Val)	EF-hand IV, Ca²⁺-chelation loop	LQTS	ADHD, dyslexia	Mildly impaired LV diastolic function, mild LA dilatation	-
*CALM1*	p.F142L (p.Phe142Leu)	EF-hand IV	LQTS	Autism, intellectual disability	Non-compaction cardiomyopathy	-
*CALM1*	p.F142L (p.Phe142Leu)	EF-hand IV	LQTS	Epilepsy, infantile spasms, EEG dysrhythmia	-	PFO, small aortopulmonary collateral from the distal arch
*CALM1*	p.F142L (p.Phe142Leu)	EF-hand IV	LQTS	Autism, intellectual disability, developmental delay, epilepsy, arachnoid cyst fenestration	-	ASD, ostium secundum
*CALM2*	p.T35I (p.Thr35Ile)	EF hand I	CPVT	Social communication disorder, gender dysphoria	-	-
*CALM2*	p.E46K (p.Glu46Lys)	EF hand II	CPVT	Autism, epilepsy with abnormal EEG	-	PDA
*CALM2*	p.E46K (p.Glu46Lys)	EF hand II	CPVT	Autism, severe intellectual disability	-	PDA
*CALM2*	p.T63R (p.Thr63Arg)	EF-hand II, Ca²⁺-chelation loop	UD	Seizures	Dilated cardiac cavities at autopsy	-
*CALM2*	p.I64M (p.Ile64Met)	EF-hand II, Ca²⁺-chelation loop	Absent	Malformation-neurodevelopmental disorder syndrome: jejunal membranous atresia, neurodevelopmental disorder, generalized joint laxity, some dysmorphic features	-	-
*CALM2*	p.N98I	EF-hand III, Ca²⁺-chelation loop	LQTS	ADHD, dyslexia, dyspraxia	Concentric LV hypertrophy
*CALM2*	p.N138K (p.Asn138Lys)	EF-hand IV, Ca²⁺-chelation loop	LQTS	Mild intellectual disability, ADHD, Rolando focus at EEG	HCM	-
*CALM3*	p.D96H (p.Asp96His)	EF-hand III, Ca²⁺-chelation loop	LQTS	Autism, developmental delay	-	PDA
*CALM3*	p.N138K (p.Asn138Lys)	EF-hand IV, Ca²⁺-chelation loop	LQTS	Psychiatric disorders	-	-
*CALM3*	p.E141G (p.Glu141Gly)	EF-hand IV, Ca²⁺-chelating	LQTS	Seizures	-	ASD
*CALM3*	p.F142L (p.Phe142Leu)	EF-hand IV	LQTS	Autism, developmental delay	RV hypertrophy & dilatation	VSD, aortic overriding

Cases with associated cardiac structural abnormalities are highlighted in grey.

ADHD, Attention deficit hyperactivity disorder; EEG, electroencephalogram; LV, left ventricle: LA, Left atrium; PFO, patent foramen ovale; ASD, atrial septal defect; PDA, patent ductus arteriosus; VSD, ventricular septal defect; RV, right ventricle; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; UD, uncertain diagnosis; CHD, congenital heart disease.

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