Systematic phenotype and genotype characterization of Moebius syndrome

To explore the phenotypic spectrum and genetic etiologies of Moebius Syndrome (MBS), a rare neurological disorder defined by congenital, nonprogressive facial weakness and limitations in ocular abduction.

We applied strict diagnostic criteria and conducted clinical phenotyping of 149 individuals with MBS. Subsequently, we performed exome and/or genome sequencing on 67 of these individuals and 117 unaffected family members.

All 149 individuals had sporadic MBS, with no recurrence within or across generations. Common co-occurring phenotypes included tongue hypoplasia (81.9%), micrognathia (66.4%), congenital talipes equinovarus (42.3%), major limb anomalies (31.5%), intellectual disability (30.9%), sleep difficulties (22.8%), and Poland anomaly (14.1%). Filtering for rare de novo or autosomal recessive single-nucleotide, insertion/deletion, and structural variants in the sequenced cohort yielded 173 single-nucleotide variant/indels in 113 genes. Although we prioritized 7 candidate genes with de novo variants and 5 with biallelic variants, no compelling recurrently mutated genes were identified. Similarly, we found no convincing variants in 2 putative genes previously implicated in MBS: PLXND1 (HGNC:9107) and REV3L (HGNC:9968).

We did not identify a strong or unifying germline genetic etiology for MBS. Future studies may explore alternative causes, including environmental exposures, somatic variants, and/or complex inheritance patterns affecting brainstem and organ embryogenesis.