REV3L – Moebius syndrome

Moebius syndrome (MBS) is a congenital disorder characterized by non-progressive facial and abducens nerve palsies. Although several candidate loci have been proposed, only dominant truncating variants in REV3L and PLXND1 are confirmed to cause MBS. Monoallelic loss-of-function in REV3L has been described in three unrelated probands, including a germline chromothriptic truncation of REV3L (PMID:31033088). A recurrent stop-gain variant, c.2662A>T (p.Lys888Ter), exemplifies the loss-of-function mechanism in MBS.

A trio-based exome study of 37 MBS and MBS-like patients failed to identify de novo REV3L variants, underscoring locus heterogeneity in this syndrome (PMID:39202332). Despite negative findings in larger cohorts, the presence of rare de novo truncating REV3L alleles supports a distinct autosomal dominant mechanism in a subset of MBS cases. Key take-home: REV3L truncating variants represent a rare but clinically actionable cause of Moebius syndrome and should be included in diagnostic gene panels.

References

• Human Mutation • 2019 • Multigenic truncation of the semaphorin-plexin pathway by a germline chromothriptic rearrangement associated with Moebius syndrome. PMID:31033088
• Unknown Journal • 2023 • Title Unavailable PMID:39202332

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