Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5–116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stopgain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ~27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late “catch-up” growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database.
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Additional Supporting Information may be found in the online version of this article. ∗Correspondence to: Matthew Lines, Metabolics, 3rd floor Max Keeping Wing, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada. E-mail: email@example.com Contract grant sponsors: Genome Canada; the Canadian Institutes of Health Research; the Ontario Genomics Institute; Ontario Research Fund; Genome Quebec; Children’s Hospital of Eastern Ontario Foundation; Resident Research Award from Physician’s Services Incorporated (PSI) Foundation.
The authors gratefully acknowledge the participation of the study participants and their families, without whom this work would not be possible. We thank Dr. Mark J. Stephan for his contribution to this work. We thank UCLA Clinical Genomics Center for their assistance with recruiting two of the individuals in this study.
© 2015 Wiley Periodicals, Inc.
- Mandibulofacial dysostosis
- Mandibulofacial dysostosis Guion-Almeida type
- Mandibulofacial dysostosis with microcephaly