Journal Article

Identification of four TTN variants in three families with fetal akinesia deformation sequence

Li, Haibo, Huang, Yingzhi, Jin, Pengzhen, Liu, Mingsong, Dong, Minyue, Liang, Yufei, Xu, Ying, Li, Zhi, Qian, Yeqing, Fan, Lihong, Shen, Xueping, Shen, Guosong

2024

Overview

Background TTN is a complex gene with large genomic size and highly repetitive structure. Pathogenic variants in TTN have been reported to cause a range of skeletal muscle and cardiac disorders. Homozygous or compound heterozygous mutations tend to cause a wide spectrum of phenotypes with congenital or childhood onset. The onset and severity of the features were considered to be correlated with the types and location of the TTN variants. Methods Whole-exome sequencing was performed on three unrelated families presenting with fetal akinesia deformation sequence (FADS), mainly characterized by reduced fetal movements and limb contractures. Sanger sequencing was performed to confirm the variants. RT-PCR analysis was performed. Results TTN c.38,876–2 A > C, a meta transcript-only variant, with a second pathogenic or likely pathogenic variant in trans , was observed in five affected fetuses from the three families. Sanger sequencing showed that all the fetal variants were inherited from the parents. RT-PCR analysis showed two kinds of abnormal splicing, including intron 199 extension and skipping of 8 bases. Conclusions Here we report on three unrelated families presenting with FADS caused by four TTN variants. In addition, our study demonstrates that pathogenic meta transcript-only TTN variant can lead to defects which is recognizable prenatally in a recessive manner.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Akinesia / Arthrogryposis - genetics / Biomedical and Life Sciences / Biomedicine / Cardiac muscle / Cardiomyopathy / Children / Congenital diseases / Connectin - genetics / Contracture - genetics / Exome Sequencing / Female / Fetal akinesia deformation sequence (FADS) / Fetus / Fetuses / Gene Expression / Genetic aspects / Genetic counseling / Genetic disorders / Genetic research / Human Genetics / Humans / Male / Meta transcript-only / Microarrays / Muscular dystrophy / Musculoskeletal system / Mutation / Neuromuscular diseases / Pedigree / Phenotypes / Physiological aspects / Polymerase chain reaction / Pregnancy / Proteins / Respiratory failure / RT-PCR / Scoliosis / Skeletal muscle / TTN / Ultrasonic imaging / Whole genome sequencing / Whole-exome sequencing