De novo mutations of are responsible for arthrogryposis broadening the -related phenotypes.

BACKGROUND

Arthrogryposis multiplex congenita (AMC) is the direct consequence of reduced fetal movements. AMC includes a large spectrum of diseases which result from variants in genes encoding components required for the formation or the function of the neuromuscular system. AMC may also result from central nervous involvement. encodes Nav1.1, a critical component of voltage-dependent sodium channels which underlie action potential generation and propagation. Variants of are known to be responsible for Dravet syndrome, a severe early-onset epileptic encephalopathy. We report pathogenic heterozygous missense de novo variants in in three unrelated individuals with AMC.

METHODS

Whole-exome sequencing was performed from DNA of the index case of AMC families. Heterozygous missense variants in (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three patients. Sanger sequencing confirmed the variants and showed that they occurred de novo.

RESULTS

AMC was diagnosed from the second trimester of pregnancy in the three patients. One of them developed drug-resistant epileptic seizures from birth. We showed that is expressed in both brain and spinal cord but not in skeletal muscle during human development. The lack of motor denervation as established by electromyographic studies or pathological examination of the spinal cord or skeletal muscle in the affected individuals suggests that AMC is caused by brain involvement.

CONCLUSION

We show for the first time that variants are responsible for early-onset motor defect leading to AMC indicating a critical role of in prenatal motor development and broadening the phenotypic spectrum of variants in .