A new patient with congenital myasthenic syndrome type 20 due to compound heterozygous missense SLC5A7 variants suggests trends in genotype–phenotype correlation

Background Congenital myasthenic syndromes (CMSs) are characterized by hypotonia, episodic apnea, muscle weakness, ptosis and generalized fatigability. CMS type 20 (CMS20) is a rare disorder caused by variants in SLC5A7. In contrast to most other CMSs, CMS20 is also associated with neurodevelopmental disorders (NDDs). Only 19 patients from 14 families have been reported so far. Methods We studied a 12‐year‐old boy with symptoms manifested at six weeks of age. Later, he also showed speech delay, moderate intellectual disability and autism. Analysis of CMS genes known at the time of clinical diagnosis yielded no results. Trio exome sequencing (ES) was performed. Results ES revealed compound heterozygosity for two SLC5A7 variants, p.(Asn431Lys) and p.(Ile291Thr). While the first variant was absent from all databases, the second variant has already been described in one patient. In silico analysis of known pathogenic SLC5A7 variants showed that variants with a higher predicted deleteriousness may be associated with earlier onset and increased severity of neuromuscular manifestations. Conclusion Our patient confirms that CMS20 can be associated with NDDs. The study illustrates the strength of ES in deciphering the genetic basis of rare diseases, contributes to characterization of CMS20 and suggests trends in genotype–phenotype correlation in CMS20. Congenital myasthenic syndrome type 20 (CMS20) is a rare autosomal recessive disorder with a neurodevelopmental component which is caused by variants in the SLC5A7 gene. We studied a 12‐year‐old boy in whom episodic apnea manifested at six weeks of age and who later developed a severe neurodevelopmental disorder. Our analysis of the current patient and all previously reported patients suggests trends in genotype–phenotype correlation in CMS20.