Mandibulofacial dysostosis with microcephaly: Mutation and database update


Lijia Huang, Children's Hospital of Eastern Ontario, Ottawa
Megan R. Vanstone, Children's Hospital of Eastern Ontario, Ottawa
Taila Hartley, Children's Hospital of Eastern Ontario, Ottawa
Matthew Osmond, Children's Hospital of Eastern Ontario, Ottawa
Nick Barrowman, Children's Hospital of Eastern Ontario, Ottawa
Judith Allanson, University of Ottawa
Laura Baker, Alfred I. duPont Hospital for Children
Tabib A. Dabir, Belfast City Hospital
Katrina M. Dipple, David Geffen School of Medicine at UCLA
William B. Dobyns, University of Washington
Jane Estrella, Westmead Hospital
Hanna Faghfoury, University Health Network University of Toronto
Francine P. Favaro, Universidade de São Paulo
Himanshu Goel, Hunter Genetics
Pernille A. Gregersen, Aarhus Universitetshospital
Karen W. Gripp, Alfred I. duPont Hospital for Children
Art Grix, Permanente Medical Group
Maria Leine Guion-Almeida, Universidade de São Paulo
Margaret H. Harr, The Children's Hospital of Philadelphia
Cindy Hudson, Shodair Children's Hospital
Alasdair G.W. Hunter, Medical Geneticist
John Johnson, Shodair Children's Hospital
Shelagh K. Joss, Queen Elizabeth University Hospital, Glasgow
Amy Kimball, Greater Baltimore Medical Center
Usha Kini, Oxford University Hospitals NHS Foundation Trust
Antonie D. Kline, Greater Baltimore Medical Center
Julie Lauzon, University of Calgary
Dorte L. Lildballe, Aarhus Universitetshospital
Vanesa López-González, Hospital Clínico Universitario Virgen de la Arrixaca
Johanna Martinezmoles, Kaiser Permanente
Cliff Meldrum, NSW Health
Ghayda M. Mirzaa, University of Washington

Document Type

Journal Article

Publication Date



Human Mutation






EFTUD2; Mandibulofacial dysostosis; Mandibulofacial dysostosis Guion-Almeida type; Mandibulofacial dysostosis with microcephaly; MFDM; Microcephaly


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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