A case of MYH3-associated contractures, pterygias and spondylocarpotarsal fusion syndrome type 1B (CPSFS1B): an example of the limitations of next-generation sequencing

Myosin heavy chain (MyHC) defects cause a variety of hereditary diseases. Phenotypic differences between various entities in this group are associated with patterns of MyHC gene expression (MYH1, MYH2, MYH3, MYH7, MYH8) in muscle cells at different stages of development. Pathogenic variants in the MYH3 gene lead to a more severe syndromic pathology characterized by short stature, scoliosis and joint contractures phenotypes. There are 4 distinctive phenotypes with their own features.

This work presents a patient with short stature, spinal anomalies, large joint contractures and clinical exome sequencing revealed a heterozygous variant c.4956+1G>A in the MYH3 gene. Because the clinical severity of the disease was more consistent with the autosomal recessive form, additional analysis of the noncoding regions of the MYH3 gene was performed, the pathogenic variant c.-9+1G>A was revealed. This example illustrates the importance to include several noncoding regions of the genome with known pathogenic variants in diagnostic panels. Furthermore, a unique feature of the patient we described is the presence of an additional cause of short stature as somatotropic deficiency.

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