Letter to the Editor
Ann Lab Med 2021; 41(6): 604-607
Published online November 1, 2021 https://doi.org/10.3343/alm.2021.41.6.604
Copyright © Korean Society for Laboratory Medicine.
A Novel TTN Gene Variant c.95136T>G (p.Cys31712Trp) and Associated Clinical Characteristics in a Family With Suspected Hereditary Myopathy With Early Respiratory Failure
Departments of 1Internal Medicine, 2Laboratory Medicine, and 3Neurology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
Correspondence to: Hyuk Sung Kwon, M.D., Ph.D.
Department of Neurology, Hanyang University College of Medicine, Hanyang University Guri Hospital, 153 Gyeongchun-ro, Guri 11923, Korea
Tel: +82-31-560-2260, Fax: +82-31-560-2289
*These authors contributed equally to this study.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Pathogenic variants of
This study was approved by the Institutional Review Board of Hanyang University Guri Hospital (2021-05-032) and informed consent was obtained from the patient. Experiments were conducted according to the Declaration of Helsinki. The proband (II-5), a 69-year-old male, was admitted to Hanyang University Guri Hospital, Guri, Korea, for vitrectomy in December 2019. He had hypertension and diabetes mellitus. He reported frequent arousal during sleep, without any respiratory symptoms. At admission, oxygen saturation was 85%, arterial pH was 7.28, arterial carbon dioxide partial pressure (PaCO2) was 74.6 mm Hg, and arterial oxygen partial pressure was 52.2 mm Hg. After the application of noninvasive ventilator support, arterial PaCO2 reached 48.3 mm Hg and pH was 7.35.
Bilateral diaphragm elevation was revealed by chest computed tomography (Fig. 1A). A pulmonary function test showed a severe restrictive pattern (Fig. 1B and 1C). Sniff test showed bilateral diaphragmatic paralysis (Fig. 1D and 1E). We observed a lack of movement on ultrasonography. Both echocardiography and electrocardiography monitoring were normal.
Figure 1. Chest images and results of pulmonary and diaphragm function tests. (A) Chest computed tomography of the proband revealed bilateral diaphragm elevation. (B, C) Pulmonary function test showed a severe restrictive pattern, with negative bronchodilator test result. Chest X-ray was performed at full inspiration (D) and full expiration (E). Sniff test showed bilateral diaphragmatic paralysis. *Percentage of measured value compared with predicted value.
Abbreviations: FEV1, forced expiratory volume in one second; FVC, forced vital capacity.
Six months later, the proband reported limb-girdle muscle weakness, but manual muscle strength was nearly normal (Medical Research Council grade 5). We found no hypertrophy or atrophy. Serum creatine kinase level was slightly elevated (3.98 μkat/L). Nerve conduction was normal. Denervation potential was noted in thoracic paraspinal muscles and the right tibialis posterior on electromyography, but we detected no myopathic abnormalities.
The proband’s 74-year-old sister (II-7) reported similar symptoms (Fig. 2A), including slowly progressive proximal and respiratory muscle weakness. Similar to the proband, her symptoms manifested at old age. She showed no definite muscle wasting or weakness. Additional information could not be obtained. The proband’s mother (I-2) and brother (II-3) had similar clinical features, including respiratory failure, and they later died due to sudden cardiac arrest.
Figure 2. Pedigree and sequence chromatogram of the novel
TTNvariant identified in the family. (A) Family pedigree. Open symbols indicate no signs or symptoms of hereditary myopathy with early respiratory failure (HMERF). Filled symbols represent affected individuals. Grey symbols indicate individuals who likely carry but were not tested for the TTNvariant. The arrow indicates the proband. (B) Results of the likely pathogenic variant of TTNfor the proband. Sequencing analysis revealed the NM_001267550.1:c.95136T>G (p.Cys31712Trp) (or NP_001243779.1:p.Cys30071Trp) variant.
Genomic DNA was extracted from peripheral blood of the proband and the proband’s sister.
Whole-exome sequencing for the proband’s sister at the Hospital of the University of Pennsylvania, Philadephia, USA, in January 2020 revealed a novel heterozygous NM_001267550.1:c.95136T>G (p.Cys31712Trp) (or NP_001243779.1:p.Cys30071Trp)
The relationships between individual pathogenic variants of
The p.Cys31712Arg variant is the most common variant in HMERF and impairs proper folding of the FN3 119 domain . The p.Cys31712Trp variant found in the current study may affect protein function and be related to a different phenotype. Titin is a giant structural muscle protein encoded by
We reported patients with a mild form of HMERF that may be associated with a novel, heterozygous, likely pathogenic variant of
All authors contributed to the conception and design of the study. Yeo Y and Park JE contributed to data acquisition, analysis, interpretation, and drafting of the initial manuscript. Kwon HS contributed to data acquisition, interpretation, and revision of the manuscript for intellectual content. All authors have read and approved the final manuscript.
CONFLICTS OF INTEREST
The authors have no conflicts of interest to report.
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