SLC18A3 – Fetal Akinesia Deformation Sequence 1

SLC18A3 encodes the vesicular acetylcholine transporter (VAChT), responsible for sequestering acetylcholine into synaptic vesicles at the neuromuscular junction, an essential step for neuromuscular transmission. Previously described SLC18A3 pathogenic variants, including missense substitutions and whole‐gene deletions, underlie presynaptic congenital myasthenic syndromes with variable postnatal presentations. Loss‐of‐function alleles have demonstrated lethal phenotypes in VAChT knockout mice, underscoring the critical requirement for transporter activity ([PMID:9873001]). Despite this, severe prenatal manifestations such as fetal akinesia deformation sequence (FADS) have not been well‐characterized. FADS and lethal multiple pterygium syndrome share overlapping clinical features, including reduced fetal movement, arthrogryposis multiplex congenita (HP:0002804), and edema (HP:0000969), but genetic etiologies often remain elusive. Inclusion of SLC18A3 in fetal diagnostic panels could therefore address a proportion of unexplained cases.

A 2019 exome sequencing study of two unrelated fetuses presenting with reduced or absent fetal movement, arthrogryposis, edema, and partial cleft palate identified a homozygous nonsense variant, c.1116C>A (p.Cys372Ter), in SLC18A3, establishing autosomal recessive inheritance of FADS ([PMID:31059209]). Segregation analysis confirmed parental carrier status, though additional affected relatives were not observed. This variant is predicted to abolish VAChT function through premature termination of translation, representing the first report of a nonsense allele in human SLC18A3. Genetic evidence remains limited with only two probands to date, meeting criteria for limited classification under ClinGen (2 probands) ([PMID:31059209]). Functional domain mapping and site‐directed mutagenesis of conserved aspartate residues in rat VAChT further emphasize the critical importance of protein integrity for acetylcholine transport, with mutation of Asp‐398 and Asp‐425 abolishing transport activity ([PMID:9873001]). Collectively, these findings support a loss‐of‐function mechanism for SLC18A3‐related FADS, though further cases and experimental validation will be required to achieve higher evidence tiers.

Key take‐home: Homozygous LoF variants in SLC18A3 cause severe prenatal FADS, supporting its inclusion in targeted prenatal genetic testing.

References

• American journal of medical genetics. Part A • 2019 • SLC18A3 variants lead to fetal akinesia deformation sequence early in pregnancy. PMID:31059209
• The Journal of biological chemistry • 1999 • Mutational analysis of aspartate residues in the transmembrane regions and cytoplasmic loops of rat vesicular acetylcholine transporter. PMID:9873001

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