Two New Mutations in MYF6 and CAPN3 Genes in a Boy with Autism Spectrum Disorder and Elevated Creatine Kinase Level

Background: Myogenic regulatory factors (MRFs) are key players in the process of myogenesis and muscle regeneration. MRFs are encoded by the family of four conserved genes: MYOD1, MYOG, MYF5, and MYF6. Although the precise role of MYF6 is not completely elucidated, it may have a critical function in differentiation and maturation of myotubes. Mutations of this gene have been reported in association with centronuclear myopathy. The CAPN3 gene provides instructions for making an enzyme called calpain-3. Although its function has not been well established, researchers suggest it may be involved in controlling the ability of muscle fibers to stretch (elasticity) and in cell signaling. CAPN3 gene mutations are the most common cause of limb-girdle muscular dystrophy.

Objective: Variants of unknown significance in the CAPN3 and MYF6 genes constitute a significant challenge for genetic counselling. In this paper, we report on the case of a patient who presented an atypical association of two mutations of these genes.

Methods and Results: The proband is a 3-year-old boy with autism spectrum disorder (ASD), speech delay and mild intellectual disability who was referred for neurogenetic evaluation due to a constant elevated CK level. Albeit, neurological examination showed no motor deficits, the muscle biopsy revealed a pattern suggestive for centronuclear myopathy. The whole exome sequencing analysis disclosed an association of two heterozygous missense mutations of MYF6 and CAPN3 genes. Both are variants of unknown significance, but the former one is correlated with the pattern observed in muscle biopsy.

Conclusion: This is the first report on a patient with ASD and intellectual disability associating mutations in MYF6 and CAPN3 genes. Further work is necessary to provide insights into the role played by these genes.