Infantile hypotonia can result from several neuromuscular disorders such as Spinal Muscle Atrophy, RASopathies and Core Myopathy with Heart Disease, to name a few. Here, we set to identify a genetic explanation for this patients infantile hypotonia.

Titin is a large sarcomeric protein that is involved with muscle contraction and sarcomere structure. Mutations in Titin have been shown to cause several myopathic and cardiomyopathic diseases. Here we present a 2-month-old female with a history of cardiac anomalies who presented to our hospital for respiratory failure and hypotonia.

Whole Exome Next Generation Sequencing results identified a previously unreported compound heterozygous mutation in Titin: c.50683_50864dupGG p.K16956Vfs*8; c.977782, p,W32594Cfs*8. The heterozygous mutations each co-segregated in her parents. Muscle biopsy demonstrated type 1 fiber predominance with moderate variation in size. NCS and EMG were non- diagnostic. Clinical evaluations indented a phenotype consisting of severely delayed milestones, non- ambulatory, arthrogryposis and respiratory failure

Here we describe a novel compound heterozygous mutation that leads to Core Myopathy with Heart Disease. Additionally, through this patient and literature review we provide an in-depth phenotypic classification of infantile Titin-opathies mutations which differs significantly from childhood or adult onset Titin-opathies.