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Calmodulin mutations associated with recurrent cardiac arrest in infants.

ABSTRACT: Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause.We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2, 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity.Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.

SUBMITTER: Crotti L

PROVIDER: S-EPMC3834768 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Calmodulin mutations associated with recurrent cardiac arrest in infants.

Crotti Lia L Johnson Christopher N CN Graf Elisabeth E De Ferrari Gaetano M GM Cuneo Bettina F BF Ovadia Marc M Papagiannis John J Feldkamp Michael D MD Rathi Subodh G SG Kunic Jennifer D JD Pedrazzini Matteo M Wieland Thomas T Lichtner Peter P Beckmann Britt-Maria BM Clark Travis T Shaffer Christian C Benson D Woodrow DW Kääb Stefan S Meitinger Thomas T Strom Tim M TM Chazin Walter J WJ Schwartz Peter J PJ George Alfred L AL

Circulation 20130206 9

<h4>Background</h4>Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause.<h4>Methods and results</h4>We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with th ...[more]

PMID: 23388215

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Project description:UnlabelledVery little is known about the psychological consequences of a cardiac arrest (CA) during childhood. Our aim was to assess long-term emotional and behavioral functioning, and its predictors, in survivors of CA in childhood. This long-term follow-up study involved all consecutive infants, children, and adolescents surviving CA in a tertiary-care university children's hospital between January 2002 and December 2011. Emotional and behavioral functioning was assessed with the Child Behavior Checklist (CBCL), Teacher's Report Form (TRF), and Youth Self-Report (YSR). Of the eligible 107 CA survivors, 52 patients, parents, and/or teachers filled out online questionnaires. Compared with normative data, parents and teachers reported significantly more attention and somatic problems (age range 6-18 years). Parents also reported more attention problems for age range 1.5-5 years. Twenty-eight percent of the children (n = 14) scored in the psychopathological range (i.e., for age range 1.5-18 years; p < 0.001) according to parent reports. Male gender, older age, and basic life support were significantly related to worse scores on the scales internalizing problems, externalizing problems, and total problems and subscale attention problems.ConclusionLong-term deficits in attention and somatic complaints were reported. Attention problems after childhood CA can interfere with school performance. Long-term follow-up with neuropsychological assessment should be organized.What is known• Critical illness has a significant influence on the presence of long-term emotional and behavioral problems. • Long-term emotional and behavioral problems have been described for various groups of critically ill children such as congenital heart disease, meningococcal septic shock, and neonatal asphyxia. What is new: • This is the first study that addresses long-term emotional and behavioral problems in a relatively large consecutive series of children and adolescents surviving cardiac arrest. • Long-term deficits in attention and somatic complaints were reported.

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Calmodulin mutations associated with recurrent cardiac arrest in infants.

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Calmodulin mutations associated with recurrent cardiac arrest in infants.

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