SLC5A7 – Congenital Myasthenic Syndrome

Recent case reports and multi‐patient studies have provided strong evidence for an association between biallelic variants in SLC5A7 and congenital myasthenic syndrome. Multiple independent reports have documented affected individuals with autosomal recessive inheritance, and the clinical presentations range from neonatal hypotonia and respiratory distress to significant developmental delays and episodic apnea (PMID:31299140, PMID:36840359). The genetic findings include missense changes and loss‐of‐function mutations that compromise the high‐affinity choline transporter’s function, a key component of neuromuscular junction transmission.

Detailed segregation analyses in familial cases further support the autosomal recessive pattern. In at least one family, segregation of a heterozygous deletion among the patient’s mother and brother reinforces the role of SLC5A7 in disease pathogenesis (PMID:38886633). Additional cases identified by trio exome sequencing have revealed compound heterozygosity for pathogenic variants, further strengthening the clinical validity of this association (PMID:36840359).

Genetic investigations have identified a diverse spectrum of SLC5A7 variants. For example, one of the recurrent mutations is reported as c.719G>A (p.Trp240Ter), a variant that appears in multiple independent studies and serves as a representative loss‐of‐function change in the affected cohorts (PMID:27569547). Other reported variant classes include missense mutations, as well as compound heterozygous changes that provide a genotype–phenotype correlation in patients with congenital myasthenic syndrome. This diversity in variant types has been critical in establishing diagnostic and counseling guidelines.

Functional studies further corroborate the pathogenicity of SLC5A7 mutations. In vitro assays have demonstrated that mutations in SLC5A7 lead to significantly decreased choline uptake activity and reduced transporter expression at the plasma membrane (PMID:12237312; PMID:23141292). These experimental findings are in concordance with the clinical phenotypes, highlighting impaired neurotransmission at the neuromuscular junction as the underlying mechanism.

The integration of genetic and experimental data provides a coherent narrative for the role of SLC5A7 in congenital myasthenic syndrome. Over 19 patients from multiple families present with consistent phenotypes and segregation patterns, and the functional studies have directly demonstrated the impact of the mutations on choline transport—the key pathogenic mechanism. Although additional evidence exists beyond the minimum scoring threshold, the combined data robustly support the clinical utility of SLC5A7 testing in individuals with CMS.

Key take‐home: The strong evidence linking biallelic SLC5A7 mutations to congenital myasthenic syndrome emphasizes its value in diagnostic decision‑making, targeted genetic counseling, and the development of future therapeutic strategies.

References

• Human Mutation • 2019 • The novel p.Ser263Phe mutation in the human high‑affinity choline transporter 1 causes a lethal form of fetal akinesia syndrome PMID:31299140
• Molecular Genetics & Genomic Medicine • 2023 • A new patient with congenital myasthenic syndrome type 20 due to compound heterozygous missense SLC5A7 variants suggests trends in genotype‑phenotype correlation PMID:36840359
• Human Molecular Genetics • 2023 • Biochemical characterization of two novel mutations in the human high‑affinity choline transporter 1 identified in a patient with congenital myasthenic syndrome PMID:36611016
• American Journal of Human Genetics • 2016 • Impaired Presynaptic High‑Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea PMID:27569547
• The Journal of Biological Chemistry • 2002 • Single nucleotide polymorphism of the human high affinity choline transporter alters transport rate PMID:12237312

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