Clinical and molecular findings in a Moroccan family with Jervell and Lange-Nielsen syndrome: a case report

Adadi et al. Journal of Medical Case Reports (2017) 11:88 DOI 10.1186/s13256-017-1243-1 CASE REPORT Open Access Clinical and molecular findings in a Moroccan family with Jervell and LangeNielsen syndrome: a case report N. Adadi1,2*, N. Lahrouchi3, R. Bouhouch4, I. Fellat4, R. Amri5, M. Alders6, A. Sefiani1,2, C. Bezzina3 and I. Ratbi2 Abstract Background: Jervell and Lange-Nielsen syndrome (Online Mendelian Inheritance in Man 220400) is a rare autosomal recessive cardioauditory ion channel disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by congenital profound bilateral sensorineural hearing loss, a long QT interval, ventricular tachyarrhythmias, and episodes of torsade de pointes on an electrocardiogram. Cardiac symptoms arise mostly in early childhood and consist of syncopal episodes during periods of stress, exercise, or fright and are associated with a high risk of sudden cardiac death. Jervell and Lange-Nielsen syndrome is caused by homozygous or compound heterozygous mutations in KCNQ1 on 11p15.5 or KCNE1 on 1q22.1-q22.2. Case presentation: We report the case of a 10-year-old Moroccan boy with congenital hearing loss and severely prolonged QT interval who presented with multiple episodes of syncope. His parents are first-degree cousins. We performed Sanger sequencing and identified a homozygous variant in KCNQ1 (c.1343dupC, p.Glu449Argfs*14). Conclusions: The identification of the genetic substrate in this patient confirmed the clinical diagnosis of Jervell and Lange-Nielsen syndrome and allowed us to provide him with appropriate management and genetic counseling to his family. In addition, this finding contributes to our understanding of genetic disease in the Moroccan population. Keywords: Jervell and Lange-Nielsen syndrome, Long QT syndrome, Deafness, Moroccan, Mutation Background Jervell and Lange-Nielsen syndrome (JLNS), Mendelian Inheritance in Man (MIM) 220400, is a rare autosomal recessive cardioauditory ion channel disorder that affects 1/200,000 to 1/1,000,000 children [1, 2]. It is characterized by congenital profound bilateral sensorineural hearing loss (SNHL), a long QT interval usually greater than 500 ms, ventricular tachyarrhythmias, and episodes of torsade de pointes on an electrocardiogram (ECG) [2, 3]. Cardiac symptoms mostly arise in early childhood and consist of syncopal episodes during periods of stress, exercise, or fright with a high risk of sudden cardiac death [2]. Homozygous or compound heterozygous loss-of* Correspondence: 1 Centre de Génomique Humaine, Faculté de Médecine et Pharmacie, Mohammed V University, Rabat, Morocco 2 Département de Génétique Médicale, Institut National d’Hygiène, Rabat, Morocco Full list of author information is available at the end of the article function mutations in KCNQ1 on 11p15.5 are responsible for 90% of cases of JLNS [4, 5]. Biallelic mutations in KCNE1 on 1q22.1-q22.2 have been identified as an additional cause of JLNS, establishing the genetic heterogeneity of the disease [6]. The two genes encode respectively the α subunits and β subunits of the voltage-gated potassium channel that in the heart conducts the slow delayed rectifying potassium ion (K+) current during cardiomyocyte repolarization, while in the ear it is involved in potassium-rich endolymph production of inner ear hair cells [5, 7]. Here we report the clinical and molecular analysis of a Moroccan family affected by JLNS. Case presentation A 10-year-old Moroccan boy was referred by his cardiologist to our medical genetics department (Institut National d’Hygiène, Rabat) for genetic evaluation. He is the firstborn of a healthy consanguineous couple (first-cousins; Fig. 1), both originating from the Northwest of Morocco. © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Adadi et al. Journal of Medical Case Reports (2017) 11:88 Page 2 of 5 Fig. 1 Pedigree of the studied family. The affected individual is shaded and indicated by an arrow. Family members that were tested for the mutation are marked by an asterisk There was no family history of sudden death, deafness, syncope, epilepsy, or any other genetic disease. The pregnancy had been medically followed, and no complications were reported. His mother presented with no history of drug ingestion or phytotherapy. His birth weight and length were within normal range and no dysmorphic signs were recorded. At 6 months, he was diagnosed as having severe bilateral SNHL on auditory evoked potential measurement. His first syncopal episode occurred at 24 months of age. His ECG revealed a markedly prolonged QTc interval of 530 ms (corrected by Bazett’s formula) and T-wave Fig. 2 Electrocardiogram of the patient alternans on V1 to V4 (Fig. 2). Echocardiography showed a structurally normal heart. Treatment was immediately started with a β-adrenergic blocker. His parents and his two younger brothers, who were 7-years old and 1-year old, were clinically normal. Blood samples from all his family’s members were collected after we were given written informed consent. Deoxyribonucleic acid (DNA) was isolated using standard techniques [8]. Molecular genetic testing of the entire coding region and flanking intronic regions of KCNQ1 and KCNE1 was undertaken by Sanger sequence analysis (details available on request). This led to Adadi et al. Journal of Medical Case Reports (2017) 11:88 the identification of a homozygous frameshift mutation c.1343dupC (p.Glu449Argfs*14) in the index patient. Both parents and one sibling (IV-2) were heterozygous for this mutation. The youngest child of the family did not carry the frameshift mutation (IV-3, Fig. 3). This variant was previously reported in a heterozygous state in an individual with long QT syndrome (LQTS) [9]. Discussion The primary electric disorders, which among others include LQTS, short-QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic Fig. 3 Electropherograms of the identified c.1343dupC; p.Glu449Argfs*14 mutation. The proband IV:1 presented with the homozygous c.1343dupC; p.Glu449Argfs*14 mutation and both parents (III:5 and III:6) and unaffected brother IV:2 are heterozygotes. One healthy brother (IV:3) was homozygous for the wild-type allele. The X indicates the position of detected mutation (Duplication of C base). The arrows indicate the location of the mutated base Page 3 of 5 ventricular tachycardia (CPVT), are often characteri (...truncated)