Systematic phenotype and genotype characterization of Moebius syndrome.
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Webb Bryn D, Jurgens Julie A, Narisu Narisu, Zhang Zhongyang, Barry Brenda J, Van Ryzin Carol, Bonnycastle Lori L, Chan Wai-Man, Yan Tingfen, Di Gioia Silvio Alessandro, Swift Amy J, MacKinnon Sarah E, Oystreck Darren T, Rucker Janet C, Frempong Tamiesha, Whitman Mary C, FitzGibbon Edmond J, Lee Janice S, Hao Ke, Andrews Caroline, Erazo Monica, Facio Flavia M, Shaaban Sherin, Naidich Thomas P, Chines Peter S, Lehky Tanya J, Toro Camilo, Gropman Andrea L, Butman John A, Zalewski Christopher K, Brewer Carmen C, Thurm Audrey, Snow Joseph, Paul Scott M, Brooks Brian P, Pierpaoli Carlo, Robson Caroline D, Hunter David G, Collins Francis S, Jabs Ethylin Wang, Engle Elizabeth C, Manoli Irini
Аннотация
METHODS: 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.
RESULTS: 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).
CONCLUSION: 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.