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

Abstract

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.

Genetic analysis of a family affected by congenital myasthenic syndrome due to a Novel mutation in the SLC5A7 gene

“…RNS tests were positive in the left common peroneal nerve, right tibial nerve, and left axillary nerve (deltoid muscle). Prior studies on six patients with SLC5A7 gene mutations [8][9][10] revealed significant reductions in low-frequency RNS in five cases. Only one case demonstrated a decrease in compound muscle action potential (CMAP) following 10 s of highfrequency RNS stimulation.…”

“…2 qPCR verification for the patient's mother and brother in exon 1, 5, and 9 of the SLC5A7 gene excitability and led to low-potassium paralytic intestinal obstruction. Recurrent intestinal perforation has been documented in related literature [10]. Thus, it is hypothesized that cholinergic neurotransmission defects may significantly contribute to gastrointestinal motility disorders and gastric perforation in patients.…”

“…The VIIa phenotype predominantly affects motor neurons, manifesting as progressive muscle weakness and atrophy in distal extremities, often with vocal cord paralysis due to vagus nerve involvement [9]. CMS20, on the other hand, may present with infantile onset apnea, cardiac arrest, muscle weakness, intermittent dysphagia, and neurodevelopmental disorders [10]. Distal hereditary motor neuropathy VIIa is caused by a frameshift mutation in the last exon of the SLC5A7 gene, leading to C-terminal truncation of CHT.…”

“…Congenital myasthenic syndrome (CMS) results from mutations in genes encoding components of the neuromuscular junction (NMJ). Clinical manifestations comprise muscle weakness, hypotonia, severe fatigue, and paroxysmal apnea [1]. Currently, 35 gene variations [2], including CHRNA1, MUSK, CHRND, COLQ, SCN4A, CHAT, SLC5A7, LAMA5, GFPT1, PURA, have been…”