TTN-Related Muscular Dystrophies, LGMD, and TMD, in an Estonian Family Caused by the Finnish Founder Variant.

IF 3 3区 医学 Q2 CLINICAL NEUROLOGY Neurology-Genetics Pub Date : 2024-10-23 eCollection Date: 2024-12-01 DOI:10.1212/NXG.0000000000200199
Katrin Õunap, Tiia Reimand, Eve Õiglane-Shlik, Sanna Puusepp, Laura Mihkla, Sander Pajusalu, Marco Savarese, Bjarne Udd
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Abstract

Background and objectives: Tibial muscular dystrophy (TMD) is an autosomal dominant, slowly progressive late-onset distal myopathy. TMD was first described in 1991 by Udd et al. in Finnish patients, who were later found to harbor a heterozygous unique 11-bp insertion/deletion in the last exon of the TTN gene-the Finnish founder variant (FINmaj). In homozygous state or compound heterozygosity with a truncating variant, the FINmaj causes early-onset recessive titin-related limb-girdle muscular dystrophy type 10 (LGMD R10). So far, the FINmaj variant has not been detected outside the Finnish population.

Methods: We describe an Estonian family presenting both early-onset LGMD R10 and late-onset TMD. The index patient underwent trio exome sequencing (ES), muscle biopsy, and RNA sequencing. The detected variants were validated by Sanger sequencing. Muscle MRI was performed in all affected individuals.

Results: Trio ES revealed 2 heterozygous variants in the TTN gene: (NM_001267550.2):c.107780_107790delinsTGAAAGAAAAA, p.(Glu35927_Trp35930delinsValLysGluLys) (FINmaj variant, paternally inherited) and (NM_001267550.2):c.64672+2dup (maternally inherited) in trans in the proband. Familial segregation analysis revealed the same biallelic variants in the younger affected sister and heterozygous FINmaj in the father. We characterized the effect of the splice variant by RNA sequencing, proving that it causes an intronic retention resulting in a premature stop codon. Muscle histology of the proband showed myopathic changes. Muscle MRI of both individuals with LGMD R10 showed early degenerative changes in tibialis anterior and in hypotrophy of distal hamstrings. Muscle MRI of the father with TMD, at the age of 38 years, showed early minimal fatty degeneration in the peroneus longus and right tibialis anterior muscles.

Discussion: For the first time, we have detected the FINmaj variant in the Estonian population. We report an Estonian family without any known Finnish ancestry for many generations, with 2 siblings harboring FINmaj in a compound with a splice site variant and their father with heterozygous FINmaj. It is currently not known whether the FINmaj is originally Estonian or Finnish ancestry. Further population studies in Estonia to establish the frequency of FINmaj in the population are ongoing and will solve the quest.

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芬兰方正变异引起的爱沙尼亚家庭ttn相关肌肉营养不良症、LGMD和TMD
背景和目的:胫肌营养不良症(TMD)是一种常染色体显性遗传、缓慢进展的晚发性远端肌病。1991 年,Udd 等人首次在芬兰患者中描述了 TMD,后来发现这些患者在 TTN 基因的最后一个外显子--芬兰始祖变体(FINmaj)中存在一个 11-bp 的插入/缺失杂合子。在同源或与截短变体复合杂合的状态下,FINmaj 会导致早发性隐性钛蛋白相关肢腰肌营养不良症 10 型(LGMD R10)。迄今为止,在芬兰以外的人群中尚未发现 FINmaj 变异:我们描述了一个同时患有早发型 LGMD R10 和晚发型 TMD 的爱沙尼亚家族。该患者接受了三组外显子测序(ES)、肌肉活检和 RNA 测序。通过桑格测序验证了检测到的变异。对所有受影响的个体进行了肌肉核磁共振成像检查:三重 ES 发现了 TTN 基因中的两个杂合变异:(NM_001267550.2):c.107780_107790delinsTGAAAGAAAAA, p.(Glu35927_Trp35930delinsValLysGluLys) (FINmaj 变异,父方遗传)和 (NM_001267550.2):c.64672+2dup (母方遗传)。家族遗传分析表明,受影响的妹妹体内存在相同的双倍变体,父亲体内存在杂合 FINmaj。我们通过 RNA 测序鉴定了剪接变体的影响,证明该变体会导致内含子滞留,造成过早的终止密码子。原发性患者的肌肉组织学检查显示有肌病变。两名 LGMD R10 患者的肌肉核磁共振成像显示,胫骨前肌和腘绳肌远端出现早期退行性病变。患有 TMD 的父亲在 38 岁时进行的肌肉磁共振成像显示,腓骨长肌和右胫骨前肌出现早期轻微脂肪变性:我们首次在爱沙尼亚人群中发现了 FINmaj 变异。我们报告了一个世代没有任何已知芬兰血统的爱沙尼亚家庭,他们的两个兄弟姐妹都携带有FINmaj,而且是一个剪接位点变异的复合体,他们的父亲是杂合子FINmaj。目前还不知道 FINmaj 的祖先是爱沙尼亚人还是芬兰人。目前正在爱沙尼亚开展进一步的人口研究,以确定 FINmaj 在人口中的频率,这将解决这一问题。
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来源期刊
Neurology-Genetics
Neurology-Genetics Medicine-Neurology (clinical)
CiteScore
6.30
自引率
3.20%
发文量
107
审稿时长
15 weeks
期刊介绍: Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.
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