P 913. Heterozygous Nonsense Variant in the TCF20 Gene as a Cause of Congenital Myopathy

Background: Early-onset myopathies represent a group of a variety of rare disorders with significant clinical and genetic heterogeneity. In the past, congenital myopathies were classified into two major groups based on histological findings:

Congenital myopathies with specific structural findings

Congenital muscular dystrophies with muscle fiber degeneration and connective tissue proliferation.

The classification of congenital myopathies with structural anomalies is based on typical histopathological findings such as cores, nemaline bodies, or central nuclei. With increasing knowledge of the genetic background, however, this strict separation can no longer be maintained in all cases. There is a significant genetic overlap between congenital myopathies with structural abnormalities and congenital muscular dystrophies.

With the increasing possibilities by new molecular genetic methods, it has become apparent that a mere morphologically based classification is no longer sufficient.

Case Report: The patient initially had very poor head control and showed delayed motor development. Sitting was possible at 13 months and walking at more than 2 years. He had a proximal muscle weakness. The child was temporarily treated with thigh-length orthoses. In the course of the disease, there was a steady improvement of muscle strength. At the age of 13 years, the gait pattern was normalized, running was possible, however, slow. Stair climbing succeeded with minor problems, getting up from the ground was possible without support. There was a weakness of the neck flexors 3/5 MRC and of the abdominal musculature 4/5 MRC. The strength of the upper limbs was unremarkable. There was neither cardiac involvement nor respiratory weakness. The boy’s length growth was along the 85th percentile.

Regarding cognition, there was a delay in language development. The boy showed some learning disabilities. There was no autism. cMRT at the age of 5 years was normal, as were repeated muscle ultrasound investigations. The family history revealed no cases of neuromuscular diseases. There was no consanguinity of the parents.

Genetics: Array CGH and fragile X diagnostics were unremarkable as was a next-generation sequencing panel comprising 98 myopathy-associated genes. An exome-wide trio analysis revealed the heterozygous de novo stop variant c.2200G>T (p.Gyl734*) in the TCF20 gene. The mutation, which was not previously described, is to be considered pathogenic according to the guidelines of the ACMG.

Therapy: The decisive consequence was the long-awaited relief for the family, finally having clarity about the etiology of the disease. Genetic counseling was now possible with estimation of the recurrence risk.

Summary and Conclusion: We report on a case with an underlying TCF20 mutation. The gene encodes the transcriptional coregulator TCF20. De novo mutations in TCF20 are so far associated with autism spectrum disorders or with intellectual disability and increased growth. The identification of the variant in a patient with an additional congenital myopathy broadens the phenotypic spectrum of TCF20-associated diseases. Additionally, this expands the spectrum of myopathy-associated genes by TCF20.