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Case Reports
. 2024 Jan 2;24(1):1.
doi: 10.1186/s12872-023-03676-z.

A novel pathogenic variant in the carnitine transporter gene, SLC22A5, in association with metabolic carnitine deficiency and cardiomyopathy features

Amir Ghaffari Jolfayi  1 , Niloofar Naderi  2 , Serwa Ghasemi  1 , Alireza Salmanipour  1 , Sara Adimi  1 , Majid Maleki  2 , Samira Kalayinia  3
Affiliations
Case Reports

A novel pathogenic variant in the carnitine transporter gene, SLC22A5, in association with metabolic carnitine deficiency and cardiomyopathy features

Amir Ghaffari Jolfayi et al. BMC Cardiovasc Disord. .

Abstract

Background: Primary carnitine deficiency (PCD) denotes low carnitine levels with an autosomal recessive pattern of inheritance. Cardiomyopathy is the most common cardiac symptom in patients with PCD, and early diagnosis can prevent complications. Next-generation sequencing can identify genetic variants attributable to PCD efficiently.

Objective: We aimed to detect the genetic cause of the early manifestations of hypertrophic cardiomyopathy and metabolic abnormalities in an Iranian family.

Methods: We herein describe an 8-year-old boy with symptoms of weakness and lethargy diagnosed with PCD through clinical evaluations, lab tests, echocardiography, and cardiac magnetic resonance imaging. The candidate variant was confirmed through whole-exome sequencing, polymerase chain reaction, and direct Sanger sequencing. The binding efficacy of normal and mutant protein-ligand complexes were evaluated via structural modeling and docking studies.

Results: Clinical evaluations, echocardiography, and cardiac magnetic resonance imaging findings revealed hypertrophic cardiomyopathy as a clinical presentation of PCD. Whole-exome sequencing identified a new homozygous variant, SLC22A5 (NM_003060.4), c.821G > A: p.Trp274Ter, associated with carnitine transport. Docking analysis highlighted the impact of the variant on carnitine transport, further indicating its potential role in PCD development.

Conclusions: The c.821G > A: p.Trp274Ter variant in SLC22A5 potentially acted as a pathogenic factor by reducing the binding affinity of organic carnitine transporter type 2 proteins for carnitine. So, the c.821G > A variant may be associated with carnitine deficiency, metabolic abnormalities, and cardiomyopathic characteristics.

Keywords: Cardiomyopathy; Organic cation transporter 2; Primary carnitine deficiency; SLC22A5; Whole-exome sequencing.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
A: The image illustrates the pedigree of the family with primary carnitine deficiency (PCD). The proband (IV-3), indicated by the arrow, is the case of the study. B: The image presents the chromatogram of the change position. The individual marked with a black dot is a homozygous carrier. + sign: the reference allele; − sign: the mutant allele
Fig. 2
Fig. 2
The image shows the proband’s cardiac magnetic resonance imaging. A, B, and C: They present 2- and 4-chamber views and short-axis short tau inversion recovery (STIR) images, respectively. Severe left ventricular enlargement is observed. D: The 4-chamber phase-sensitive inversion recovery (PSIR) with a 10-minute delay demonstrates no abnormal enhancement. Increased signal intensity adjacent to the subendocardial muscles in the STIR images is secondary to a significantly reduced ejection fraction and subsequent blood stasis
Fig. 3
Fig. 3
The images illustrate (A) the interaction between the wild-type protein and L-carnitine, (B) the interaction between the mutant protein and L-carnitine, (C) the 3D structure of normal organic carnitine transporter type 2 (OCTN2) (green) in interaction with L-carnitine, and (D) the 3D structure of the mutant OCTN2 (blue) in interaction with L-carnitine
See this image and copyright information in PMC

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