Four patients from three families had severe congenital weakness requiring support for breathing and feeding in the Neonatal Intensive Care Unit.  One patient passed at 6 weeks of age in the NICU after his family opted not to pursue intubation when noninvasive ventilation was no longer sufficient for him.  The other patients were supported with tracheostomies and gastrostomies.  Two patients underwent NCS/EMG and muscle biopsy which revealed nonspecific myopathic results with possible dystrophic features.  The three living patients were delayed in motor milestone acquisition but achieved ambulation in early childhood.  They went through mainstream schooling and had tracheostomies and gastrostomies removed in childhood.  They now exhibit moderate facial and proximal limb weakness, and they continue to be ambulatory in adolescence and adulthood without evidence of progressive weakness.   Invitae Comprehensive Neuromuscular Disorders Panel identified novel homozygous pathogenic variants at a splice site in CACNA1S in all four patients: c.3414+3A>T (intronic).

The scarcity of reported cases involving pathogenic CACNA1S variants with congenital myopathy has left gaps in our understanding of the disease's natural history.  Our patients demonstrate severe congenital weakness followed by improvement in strength and normal cognition.  We propose the novel splice site variant found in these patients is the etiology of the unique clinical phenotype.  Exploring these cases enhances our knowledge of phenotypic spectrums and serves as a foundation for future treatment development.