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Year : 2018  |  Volume : 7  |  Issue : 3  |  Page : 170-173

Neonatal brief resolved unexplained events like episode associated with long QT syndrome and novel missense mutation (Thr1502Ile)

1 Department of Peds and Neonatology, Dr LH Hiranandani Hospital, Mumbai, Maharashtra, India
2 Department of Pediatric Cardiology, Dr LH Hiranandani Hospital, Mumbai, Maharashtra, India

Date of Web Publication2-Aug-2018

Correspondence Address:
Dr. Niraj Kumar Dipak
Department of Peds and Neonatology, Dr LH Hiranandani Hospital, Powai, Mumbai - 400 076, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_132_17

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Fetal and neonatal manifestations of long QT syndrome are not well documented except few case reports. We report a neonate presenting with potential brief resolved unexplained events like episode, long QT interval was noted on surface electrocardiogram, and molecular diagnosis revealed a novel heterozygous nonsynonymous missense substitution in exon 17 of the A-kinase anchor protein 9 gene. The proband responded to propranolol at a dose of 1 mg/kg/day.

Keywords: A-kinase anchor protein 9 gene, brief resolved unexplained events, long QT syndrome, missense mutation

How to cite this article:
Dipak NK, Garekar S, Pandya S, More SM. Neonatal brief resolved unexplained events like episode associated with long QT syndrome and novel missense mutation (Thr1502Ile). J Clin Neonatol 2018;7:170-3

How to cite this URL:
Dipak NK, Garekar S, Pandya S, More SM. Neonatal brief resolved unexplained events like episode associated with long QT syndrome and novel missense mutation (Thr1502Ile). J Clin Neonatol [serial online] 2018 [cited 2022 Aug 9];7:170-3. Available from: https://www.jcnonweb.com/text.asp?2018/7/3/170/238397


Fetal and neonatal manifestations of long QT syndrome (LQTS) are less well characterized and documented barring few case reports. LQTS is caused by mutations of at least 15 different genes, but KCNQ1, KCNH2, and SCN5A account for >90% of the occurrence.[1] There is somewhat predictability in the association between a patient's genotype and phenotype, and specific gene mutations are correlated with specific phenotype in LQTS. As a group, it is considered as genetically heterogeneous, meaning thereby, the same disorder is caused by mutations in different genes. In addition, LQTS is characterized by variable expression and incomplete penetrance and associated with a high degree of unexplained phenotypic variability, that is, wide range of heart rate-corrected QT interval duration (QTc), the incidence of cardiac events (sudden death, aborted cardiac arrest, and syncope), and age of the first clinical manifestation, even with the same primary disease-causing mutation.

High-risk cases of LQTS for cardiac events in neonatal age group are those associated with atrioventricular (AV) block leading to bradycardia, torsades de pointes, long QTc (>600 ms), ventricular fibrillation, and mutations involving human ether-a-go-go-related gene (hERG) and SCN5A genes.[2],[3] Cardiac events (sudden death, Brugada syndrome or sudden unexpected nocturnal death syndrome, and near-miss sudden infant death syndrome)[4] in fetal and neonatal period are higher with mutations in SCNA5 and hERG genes. We are reporting a neonate who presented with potential brief resolved unexplained events (BRUE) like episode, long QT interval was noted on the surface electrocardiogram (ECG), and molecular diagnosis revealed a novel heterozygous nonsynonymous missense substitution in exon 17 of the A-kinase anchor protein 9 (AKAP9) gene.

[TAG:2]Case Report[/TAG:2]

A 19 days- old female baby was brought to Accident and Emergency Department by parents with a history of complete unresponsiveness at home for about 30 min. During that episode, the baby was pale and flaccid and had somewhat decreased breathing as perceived by the mother. She was awake before the event. By the time she reached the medical facility, she regained consciousness gradually without any intervention after nearly 30 min. The baby was admitted in Neonatal Intensive Care Unit for continuous pulse oximetry and serial observation. The baby was full term, born through lower-segment cesarean section in view of preeclampsia, and cried immediately after birth. Birth weight was 2.93 kg and was on exclusive breastfeeding till the time of admission. It was the first child of parents and the marriage was nonconsanguineous. Pregnancy was in vitro fertilization conception with twin pregnancy and embryo reduction was done in view of oligohydraminos in one sac with growth restriction at 20 weeks of gestation. Karyotype from reduced fetus done in view of isolated fetal growth restriction was normal. Inborn errors of metabolism screening sent before discharge was normal. There was no history of cardiac disease at early age, seizures, repeated pregnancy loss, neonatal deaths, or sudden cardiac death in family members.

On admission with history of postpotential BRUE, the baby was back to normal consciousness and breathing but was noted to have excessive cry and tachycardia. Chest X-ray (CXR), venous blood gas, complete blood count, random blood glucose, partial sepsis screen, electrolytes, serum calcium, serum magnesium, electroencephalography, ultrasonography (USG) skull, and two-dimensional ECHO were normal.

Surface ECG revealed prolonged QTc interval >480 ms. Repeat ECG at 24 h showed further prolongation of QTc to >490 ms [Figure 1]. The infant was started on propranolol at a dose of 1 mg/kg/day. Report of hearing screening by BERA was PASS in both the ears. Both mother and father had normal QTc on surface ECG.
Figure 1: Lead II showing long corrected QT interval

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Molecular diagnosis revealed a heterozygous nonsynonymous missense substitution in exon 17 of the AKAP9 gene (chr7:91667899; C > C/T) that results in the amino acid substitution of isoleucine for threonine at codon 1502 (p. Thr1502Ile). Thr1502Ile variant has not been reported in both the 1000 genomes and ExAC databases. Validation of the variant by Sanger sequencing was done to rule out false positives. Neither parent had this mutation (chr7:91667899; C > C/T) and no additional sequence variations were found.

At the timing of writing of this article, she is 5 months old with normal growth and development. Her QTc is 0.41 s and remained largely asymptomatic since discharge.


The proband in this case presented with potential BRUE[5] with high-risk category (age <60 days, duration of event >1 min), which led us to do the relevant investigations including ECG, in addition to infection screen, blood glucose, CXR, and USG skull.

LQTS has been described in fetal (intrauterine fetal death, sinus bradycardia, AV conduction block, and ventricular tachycardia)[6],[7] and perinatal period (sudden cardiac death, AVB, and torsade de pointes).[3],[7],[8]De novo mutations have been reported in neonates who had mutations in either the sodium channel gene SCN5A or the potassium channel gene KCNH2,[3] but de novo mutation involving AKP9 gene is not described earlier. [Table 1] shows the reported clinical and genetic characteristics of neonatal LQTS. Mutations in one of the 15 different ion-channel genes can cause LQTS. [Table 2] depicts the LQTS types 1-15 and their corresponding genes.[1] The remaining mutations are de novo and account for <5% of cases. Some of these variants have only been described in a few individuals. Those isolated cases with no family history of the syndrome represent either the sporadic occurrence of a new mutation or incomplete penetrance. Genetic diagnosis reveals a number of asymptomatic family members carrying the mutation.
Table 1: Characteristics of neonates with long QT syndrome

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Table 2: Long QT syndrome types 1-15 and their corresponding genes

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AKAP9 gene consists of 50 exons and encodes a protein of 3907 amino acids, and only one pathogenic missense variant (S1570 L) in AKAP9 associated with LQTS has been described.[10] It produces a kinase (prka) anchor protein (AKAP, Yotiao). Yotiao forms a macromolecular complex with voltage-gated potassium channel α-subunits. Pathogenic loss-of-function variant results in an IK channel with reduced function, further leading to increased risk of sudden death and BRUE-like episodes.

Till date the accumulated scientific evidence emphasizes the role of AKAP9 gene as a gene modifier in which it was present along with causative known 15 genes for LQTS and LQTS 11 [Of which, only one family reported till date, proband-a 13 year old caucasian girl with (S1570L)] substitution.[11] de Villiers et al.[11] found AKAP9 gene contributing to LQTS phenotypic variability in different members of a South African LQTS-type 1 founder population. Considering the rarity of AKP9 gene (described in only 1 family) and novel de-novo mutation (p. Thr1502Ile) and resulting severity of phenotypic manifestation (neonatal BRUE like episode), molecular diagnosis is of value to support the clinical diagnosis.

Treatment of choice for most LQTS in neonates even in asymptomatic ones is beta-receptor blockers and proband in our case responded to propranolol. Whether treatment of neonatal manifestations of LQTS varies in relation to specific genotype is subjected to accumulating scientific evidence, and so far only limited data are available.[12],[13]

Molecular diagnosis places this missense de novo mutation (p. Thr1502Ile) most closely to LQTS-type 11, which involves AKAP9 gene on ch7 q21-22. As per the current existing knowledge, alteration in AKAP9 gene (LQTS 11) is poorly characterized (i.e., what are its trigger factors, symptomatic or asymptomatic manifestation, and if symptomatic, then age of presentation?) and its occurrence is <1%.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000;102:1178-85.  Back to cited text no. 1
Lupoglazoff JM, Denjoy I, Villain E, Fressart V, Simon F, Bozio A, et al. Long QT syndrome in neonates: Conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations. J Am Coll Cardiol 2004;43:826-30.  Back to cited text no. 2
Wedekind H, Smits JP, Schulze-Bahr E, Arnold R, Veldkamp MW, Bajanowski T, et al. De novo mutation in the SCN5A gene associated with early onset of sudden infant death. Circulation 2001;104:1158-64.  Back to cited text no. 3
Skinner JR, Chung SK, Montgomery D, McCulley CH, Crawford J, French J, et al. Near-miss SIDS due to Brugada syndrome. Arch Dis Child 2005;90:528-9.  Back to cited text no. 4
Tieder JS, Bonkowsky JL, Etzel RA, Franklin WH, Gremse DA, Herman B, et al. Brief resolved unexplained events (Formerly apparent life-threatening events) and evaluation of lower-risk infants. Pediatrics 2016;137. pii: e20160590.  Back to cited text no. 5
Hosono T, Kawamata K, Chiba Y, Kandori A, Tsukada K. Prenatal diagnosis of long QT syndrome using magnetocardiography: A case report and review of the literature. Prenat Diagn 2002;22:198-200.  Back to cited text no. 6
Schulze-Bahr E, Fenge H, Etzrodt D, Haverkamp W, Mönnig G, Wedekind H, et al. Long QT syndrome and life threatening arrhythmia in a newborn: Molecular diagnosis and treatment response. Heart 2004;90:13-6.  Back to cited text no. 7
Beery TA, Shooner KA, Benson DW. Neonatal long QT syndrome due to a de novo dominant negative hERG mutation. Am J Crit Care 2007;16:416, 412-5.  Back to cited text no. 8
Bond R, Blaufox A, Goldner B, Patel A. Congenital long QT syndrome: A case report of LQT2 and LQT13 in a neonate. Europace 2014;16:1807.  Back to cited text no. 9
Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS, et al. Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci U S A 2007;104:20990-5.  Back to cited text no. 10
de Villiers CP, van der Merwe L, Crotti L, Goosen A, George AL Jr., Schwartz PJ, et al. AKAP9 is a genetic modifier of congenital long-QT syndrome type 1. Circ Cardiovasc Genet 2014;7:599-606.  Back to cited text no. 11
Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, et al. Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103:89-95.  Back to cited text no. 12
Priori SG. Gene specific therapy for cardiac disease: The case of long QT syndrome. Rev Port Cardiol 1998;17 Suppl 3:III27-38.  Back to cited text no. 13


  [Figure 1]

  [Table 1], [Table 2]


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