search for


Identification of LAMP2 mutations in early-onset hypertrophic cardiomyopathy by targeted exome sequencing
Journal of Genetic Medicine 2018;15:87-91
Published online December 31, 2018;
© 2018 Korean Society of Medical Genetics and Genomics.

Inkyu Gill, Ja Hye Kim, Jin-Hwa Moon, Yong Joo Kim, and Nam Su Kim

Department of Pediatrics, Hanyang University College of Medicine, Seoul, Korea
*Nam Su Kim, M.D.,, Department of Pediatrics, Hanyang University Seoul Hospital, Hanyang University College of Medicine, 222-1 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea. Tel: +82-2-2290-8389, Fax: +82-2-2297-2380, E-mail:
Received May 18, 2018; Revised July 28, 2018; Accepted July 31, 2018.
cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

X-linked dominant mutations in lysosome-associated membrane protein 2 (LAMP2) gene have been shown to be the cause of Danon disease, which is a rare disease associated with clinical triad of cardiomyopathy, skeletal myopathy, and mental retardation. Cardiac involvement is a common manifestation and is the leading cause of death in Danon disease. We report a case of a 24-month-old boy with hemizygous LAMP2 mutation who presented with failure to thrive and early-onset hypertrophic cardiomyopathy. We applied targeted exome sequencing and found a novel hemizygous c.692del variant in exon 5 of the LAMP2 gene, resulting a frameshift mutation p.Thr231Ilefs*11. Our study indicates that target next-generation sequencing can be used as a fast and highly sensitive screening method for inherited cardiomyopathy.

Keywords : Lysosomal-associated membrane protein 2, Danon disease, Hypertrophic cardiomyopathy, Whole exome sequencing

Danon disease is a rare X-linked dominant disorder, initially described in two boys presenting with cardiomyopathy, skeletal myopathy, and mental retardation [1]. This disease is caused by mutations in lysosome-associated membrane protein 2 (LAMP2) gene located at Xq24 [2]. Major clinical findings include skeletal and cardiac myopathy, cardiac conduction abnormalities, intellectual difficulties, and retinal involvement [3]. Cardiac involvement is the leading cause of death in patients with Danon disease [4]. Early diagnosis is important for family counseling, but molecular diagnosis is difficult because of genetic heterogeneity of cardiomyopathy. With advances of next-generation sequencing (NGS), massive parallel sequencing of multiple genes facilitates confirmative genetic approach to patients with cardiomyopathy [57]. We report the case of a 24-month-old boy with hemizygous LAMP2 mutation who presented with failure to thrive and early-onset of hypertrophic cardiomyopathy (HCMP).


A 24-month-old boy visited our endocrinology clinic, concerned with short stature and poor weight gain. His height was 78.9 cm (–2.03 standard deviation scroe [SDS]) and his weight was 9.2 kg (–2.66 SDS). He was born at 38 weeks gestation with 2.64 kg (–1.71 SDS) from non-consanguineous and healthy parents. He had an admission history of neonatal intensive care unit for transient tachypnea at newborn. On physical examination, there was no evidence of muscle weakness and dysmorphic morphology. His development was normal. Laboratory findings including white blood cell of 10,100/mm3, hemoglobin of 13.6 g/dL, platelets of 360,000/mm3, thyrotropin stimulating hormone of 2.05 μIU/mL, and free T4 of 1.54 ng/dL were unremarkable, but elevated levels of aspartate aminotransferase (161 U/L) and alanine aminotransferase (88 U/L) were noted. Viral studies such as hepatitis virus A, hepatitis virus B, hepatitis virus C, Epstein-Barr virus, and cytomegalovirus were negative. Elevated liver enzymes persisted and elevated creatinine kinase (337 U/L) was remarked. So he was referred to the pediatric neurology clinic to evaluate neuromuscular disease.

He had motor grade of 5 in all limbs with normal muscle mass and muscle tone. The deep tendon reflex was normal and there was no Gower’s sign. He was able to walk independently in a normal gait. His neurology examination revealed no special findings. Developmental milestones in all categories were not delayed, including gross and fine motor milestones. A harsh grade 2 systolic murmur was denoted on the apex area of left anterior chest with regular heartbeat, therefore he was consulted to the pediatric cardiology clinic. The electrocardiogram showed biventricular hypertrophy with high voltage on every chest lead. Echocardiography showed thickened posterior wall of left ventricle and septum with normal systolic function and diastolic dysfunction (Fig. 1).

We initially performed metabolic assessment to distinguish inherited metabolic cardiomyopathy including fatty acid oxidation disorders and Pompe disease. However, serum amino acid analysis, urine organic acid analysis, acylcarnitine profiles, and molecular analysis of GAA gene results were all unremarkable. Then, we applied targeted exome sequencing to identify monogenic disorders of congenital cardiomyopathy using the MiSeq platform (Illumina, Inc., San Diego, CA, USA) and the TruSight One Sequencing panel (Illumina, Inc.). This panel contains multiple cardiomyopathy-related genes that have been previously reported to be associated with HCMP; the genes related with sarcomere proteins, the genes related with inherited left ventricular hypertrophy, the genes related with syndromic disease with cardiomyopathy, the genes related with metabolic cardiomyopathy, and the genes related with neuromuscular disorders (Table 1). Using these analyses, we identified a novel hemizygous for c.692del variant in exon 5 of the LAMP2 gene, resulting in a frameshift mutationp.Thr231Ilefs*11 (Fig. 2). His mother was not a carrier of the mutation. No retinal abnormalities were detected at ophthalmic examination.


This case illustrated the clinical efficacy of targeted exome sequencing in patients with HCMP. Usually, Danon disease is presented with cardiomyopathy, skeletal myopathy and varying degree of intellectual disabilities, however in our case, the patient only manifested with early-onset HCMP. Although this condition is a syndromic disease, it is not easy to approach the diagnosis if only one clinical symptom is developed. Therefore, NGS can be an effective diagnostic tool of HCMP.

Cardiomyopathy in Danon disease is progressive, and it develops early as a hypertrophic phenotype. The age at cardiac presentation of Danon disease varied from infancy to the second decade of life in men, and sudden death may occur in patients with this disease in the second or third decade of life. Also, affected males have learning disability or cognitive problems in 70–100% [3,4]. Skeletal myopathy is also cardinal feature, which denotes progressive proximal muscle weakness of the shoulders, neck, and legs in 80–90% of males [4]. The therapeutic option for Danon disease was limited, but cardiac transplantation enhances the survival of patients [8].

Since the outcome of HCMP in childhood varies by its underlying disease and age at diagnosis, early detection and diagnosis is important [9]. HCMP in childhood is genetically heterogeneous with many different genes [10]. It can also manifest systemic features affecting non-cardiac organs. Because of these diverse causes, genetic testing is recommended with high level of evidence along with the metabolic work-up in many guidelines [11,12]. In previous studies, 40–60% of the cause for HCMP was mainly mutations in cardiac sarcomere protein genes using single gene or multiple panel testing by Sanger sequencing [11,13,14]. Traditional method to diagnose Danon disease was to confirm the histological and immunohistochemistry findings, such as vacuolation of muscle fibers and absence of LAMP2 protein, respectively, through the muscle biopsy. Recently, NGS has been an advanced diagnostic tool to evaluate the cause of cardiomyopathy. Not only it reduced the turn-around-time compared to the traditional method, but it also increased the diagnostic yield, and enabled to avoid invasive technique necessary for diagnosis such as skeletal/cardiac muscle biopsy [6,15]. Recent reports on congenital cardiomyopathy including Danon disease using the NGS method are increasing [7].

To date, more than 90 different disease-causing mutations have been reported ( Nonsense and frameshift mutations are common types of mutations resulting truncate the LAMP2 protein. TheLAMP2p.Thr231Ilefs*11 variant is a novel frameshift mutation located on topological domain. This variant is not present in 1000Genomes browser (, NHLBI ESP Exome Variant Server ( and genome Aggregation Database (gnomAD; This variant is classified as pathogenic according to the guideline of the American College of Medical Genetics Laboratory Practice Committee Working Group [16].

In conclusion, we report a novel mutation inLAMP2 gene and our study indicates that target NGS provides a rapid and highly sensitive screening method for the inherited cardiomyopathy.

Fig. 1.

(A) Hypertrophy of septum (arrows) and posterior wall of left ventricle (arrowheads) by subcostal four chamber view by echocardiography. (B) Thickened septum and posterior wall of left ventricle with normal systolic function.

Fig. 2.

Pedigree of the patient and the partial DNA sequence of LAMP2 gene of patient and his mother; novel hemizygous c.692del variant (p.Thr231Ilefx*11) in exon 5 of the LAMP2 gene.


Congenital cardiomyopathy gene list included in current panel

Etiology Gene symbol Description
Hypercardiotrophic sacromere proteins MYH7 β-Myosin heavy chain
MYBPC3 Cardiac myosin-binding protein C
TNNT2 Cardiac troponin T
TNNI3 Cardiac troponin I
TPM1 α-Tropomyosin
MYL2 Regulatory myosin light chain
MYL3 Essential myosin light chain
ACTC1 α-Cardiac actin
ACTN2 α-Actinin 2
MYH6 Myozenin-2
TCAP Telethonin
TNNC1 Troponin C, slow skeletal and cardiac muscles
PLN Cardiac phospholamban
MYOZ2 Myozenin-2
NEXN Nexilin

Inherited left ventricular hypertrophy CSRP3 Muscle LIM protein
PRKAG2 AMP-activated protein kinase mutation, WPW syndrome
LAMP2 Danon disease

Multiple congenital anomaly syndrome PTPN11 Noonan syndrome, LEOPARD syndrome
H19 Beckwith-Wiedemann syndrome
KCNQ1 Beckwith-Wiedemann syndrome
CDKN1C Beckwith-Wiedemann syndrome
HRAS Costello syndrome
CREBBP Rubinstein-Taybi syndrome
BRAF Cardiofaciocutaneous syndrome

Inborn errors of metabolism GAA Pompe disease
IDUA Hurler syndrome (mucopolysaccharidosis type I)
IDUA Scheie syndrome
GLA Fabry disease
MAN2B1 Mannosidosis
MUT Methylmalonic aciduria

Mitochondrial disorders NDUFS4 Leigh syndrome, complex I deficiency
NDUFA2 Leigh syndrome, complex I deficiency
NDUFS3 Leigh syndrome, complex I deficiency
NDUFS7 Leigh syndrome, complex I deficiency
NDUFA2 Leigh syndrome, complex I deficiency
ACADVL Very long chain acyl-coenzyme A dehydrogenase deficiency
HADHA Long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency

Neuromuscular disorders FXN Friedreich ataxia
DMPK Myotonic dystrophy
RYR1 Minicore (multicore) myopathy

LIM, lin-11, islet-1, mec-3; AMP, adenosine monophosphate; WPW, Wolff-Parkinson-White; LEOPARD, lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness.

  1. Danon, MJ, Oh, SJ, DiMauro, S, Manaligod, JR, Eastwood, A, and Naidu, S (1981). Lysosomal glycogen storage disease with normal acid maltase. Neurology. 31, 51-7.
    Pubmed CrossRef
  2. Nishino, I, Fu, J, Tanji, K, Yamada, T, Shimojo, S, and Koori, T (2000). Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 406, 906-10.
    Pubmed CrossRef
  3. Sugie, K, Yamamoto, A, Murayama, K, Oh, SJ, Takahashi, M, and Mora, M (2002). Clinicopathological features of genetically confirmed Danon disease. Neurology. 58, 1773-8.
    Pubmed CrossRef
  4. Boucek, D, Jirikowic, J, and Taylor, M (2011). Natural history of Danon disease. Genet Med. 13, 563-8.
    Pubmed CrossRef
  5. Szabadosova, V, Boronova, I, Ferenc, P, Tothova, I, Bernasovska, J, and Zigova, M (2018). Analysis of selected genes associated with cardiomyopathy by next-generation sequencing. J Clin Lab Anal. in press
    Pubmed CrossRef
  6. Cecconi, M, Parodi, MI, Formisano, F, Spirito, P, Autore, C, and Musumeci, MB (2016). Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy. Int J Mol Med. 38, 1111-24.
    Pubmed KoreaMed CrossRef
  7. Fu, L, Luo, S, Cai, S, Hong, W, Guo, Y, and Wu, J (2016). Identification of LAMP2 mutations in early-onset Danon disease with hypertrophic cardiomyopathy by targeted next-generation sequencing. Am J Cardiol. 118, 888-94.
    Pubmed CrossRef
  8. Maron, BJ, Roberts, WC, Arad, M, Haas, TS, Spirito, P, and Wright, GB (2009). Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA. 301, 1253-9.
    Pubmed KoreaMed CrossRef
  9. Colan, SD, Lipshultz, SE, Lowe, AM, Sleeper, LA, Messere, J, and Cox, GF (2007). Epidemiology and cause-specific outcome of hypertrophic cardiomyopathy in children: findings from the pediatric cardiomyopathy registry. Circulation. 115, 773-81.
    Pubmed CrossRef
  10. Moak, JP, and Kaski, JP (2012). Hypertrophic cardiomyopathy in children. Heart. 98, 1044-54.
    Pubmed CrossRef
  11. Elliott, PM, Anastasakis, A, Borger, MA, Borggrefe, M, Cecchi, F, and Charron, P (2014). 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the task force for the diagnosis and management of hypertrophic cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 35, 2733-79.
    Pubmed CrossRef
  12. Gersh, BJ, Maron, BJ, Bonow, RO, Dearani, JA, Fifer, MA, and Link, MS (2011). 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation. 124, 2761-96.
    Pubmed CrossRef
  13. Van Driest, SL, Ommen, SR, Tajik, AJ, Gersh, BJ, and Ackerman, MJ (2005). Yield of genetic testing in hypertrophic cardiomyopathy. Mayo Clin Proc. 80, 739-44.
    Pubmed CrossRef
  14. Morita, H, Rehm, HL, Menesses, A, McDonough, B, Roberts, AE, and Kucherlapati, R (2008). Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med. 358, 1899-908.
    Pubmed KoreaMed CrossRef
  15. Lee, TM, Hsu, DT, Kantor, P, Towbin, JA, Ware, SM, and Colan, SD (2017). Pediatric cardiomyopathies. Circ Res. 121, 855-73.
    Pubmed KoreaMed CrossRef
  16. Richards, S, Aziz, N, Bale, S, Bick, D, Das, S, and Gastier-Foster, J (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 17, 405-24.
    Pubmed KoreaMed CrossRef

June 2019, 16 (1)
Full Text(PDF) Free

Social Network Service

Cited By Articles
  • CrossRef (0)

Author ORCID Information