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Dear Editor, Titinopathies are a group of clinical and pathologically heterogeneous muscle disorders. These diseases have been frequently reported in the Finnish population, but have been rarely found in Asian populations.1 We previously reported recessive TTN variants as the genetic cause in a large Korean cohort of inherited muscular disorders.2 However, the detailed clinical phenotype was not investigated. Here we present clinical and pathological findings of a Korean family with rigid spine syndrome and respiratory difficulty carrying pathogenic variants of TTN. The proband (a 43-year-old man) (Fig. 1A and B, II-5) complained of muscle weakness, scoliosis, and respiratory difficulty. He demonstrated muscle weakness, faint crying, and weak sucking at birth. Since childhood he had experienced difficulty in bending his neck and spine. He was first hospitalized at the age of 30 years for respiratory difficulty, since when he used noninvasive positive pressure ventilation via a nasal mask intermittently, mainly at nighttime. When we examined him at the age of 43 years, he could walk independently. He displayed proximal weakness, lordosis, scoliosis, ankle contracture, and limited bending of the neck (Fig. 1C). He did not have extraocular movement limitation or craniofacial dysmorphism. His forced vital capacity was 0.76 L (20%), his PaCO2 was 47.4 mm Hg, and his serum creatine kinase level was 89 IU/L (reference value <185 IU/L). The electromyography findings were compatible with chronic myopathy, while his electrocardiography and echocardiography findings were normal. A biceps brachii muscle biopsy was performed when he was 30 years old. Staining with hematoxylin and eosin revealed moderate variations of fiber size and shape, in addition to many fibers having internalized nuclei (Fig. 1D). Intracytoplasmic inclusions and subsarcolemmal depositions were not found by modified Gomori trichrome staining (Fig. 1E). Staining with nicotinamide adenine dinucleotidetetrazolium reductase revealed that type I fibers predominated (Fig. 1F). The older sister of the proband (a 50-year-old woman) (Fig. 1A and B, II-2) had a similar clinical presentation that included proximal weakness, lordosis, scoliosis, ankle contracture, and limited bending of the neck. Although she did not use a ventilator, she experienced morning headaches and daytime somnolence. Her forced vital capacity was 0.8 L (22%) and she exhibited limited extraocular movement. We performed targeted sequencing of 69 myopathy-related genes, including TTN, to obtain a confirmative diagnosis in the proband (Supplementary Table 1, 2, and 3 in the onlineonly Data Supplement). We identified two compound heterozygous TTN variants: c. 143722A>G and c.102523C>T (Fig. 1B) (Supplementary Information in the online-only Data Supplement). Capillary sequencing showed that the TTN variants cosegregated completely with the two affected family members (Fig. 1A and B). The c.14372-2A>G variant has previously been reported as a pathogenic variant,3 while the c.102523C>T (p.Arg34175*) variant is a novel truncating variant that was not found in 298 healthy controls, the dbSNP138 Hyung Jun Park Jung Hwan Lee Se Hoon Kim Ji-Man Hong Ha Young Shin Seung Min Kim Ji Hyun Lee Kee Duk Park Young-Chul Choi

Clinical and Pathological Findings of a Korean Family with Pathogenic Variants of the TTN Gene