CONGENITAL MYOPATHIES 2: P.93 Novel TTN variants identified by whole exome sequencing in patients with prenatal onset titinopathy

Abstract

The TTN gene encodes the largest human protein, titin, which is of functional and structural importance at the sarcomere. Pathogenic variants in TTN have been reported for a variety of skeletal muscle disorders and cardiomyopathies and exhibit both autosomal dominant and recessive inheritance. Next generation sequencing (NGS) and whole exome sequencing (WES) have allowed for routine sequencing of a large number of genes, including the full TTN gene. These advancements have helped to delineate the phenotypic spectrum in patients with mutations in several neuromuscular genes, including TTN. In 2014, the first patient with arthrogryposis multiplex congenita (AMC) and pathogenic variants in TTN was reported, but additional published cases are limited. Utilizing WES, we have identified four unrelated cases in which the proband presented prenatally or neonatally with features suggestive of a severe neuromuscular condition such as polyhydramnios, hydrops fetalis, talipes equinovarus, arthrogryposis, hypotonia, and/or respiratory insufficiency. In one of these cases, the maternal family history was also suggestive for dilated cardiomyopathy in two siblings. Case one - homozygous c.25063+1G>A (I-band). Case two - c.100296dup (p.Glu33433*, M-band) and c.36402del (p.Val12135Cysfs*23, I-band). Case three - c.38442dupA (p.Pro12815Thrfs*37, I-band) and c.88594+1G>T (A-band). Case four has a maternally inherited c.61921C>T (p.Arg20641*, A-band); however, a second paternal variant was not identified. Although truncating variants in the Z-disc, I-band and M-band in TTN may not confer cardiomyopathy risk, some of these variants may be pathogenic for severe, recessive neuromuscular conditions. TTN variants, in particular protein truncating variants, should be considered in cases of lethal congenital contracture syndrome, AMC, congenital myopathies, and hydrops fetalis. These cases expand our knowledge and understanding of the more severe phenotypic spectrum for titinopathies.