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Mandibulofacial dysostosis with microcephaly: mutation and database update

Mandibulofacial dysostosis with microcephaly: mutation and database update
Mandibulofacial dysostosis with microcephaly: mutation and database update
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, U5-116kDa / 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 7 microdeletions. Among point mutations, missense substitutions are infrequent (14/76; 18%) relative to stopgain (29/76; 38%), and splicing (33/76; 43%) mutations. Where known, mutation origin was de novo in 48/64 individuals (75%), dominantly-inherited in 12/64 (19%), and due to proven germline mosaicism in 4/64 (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 (http://databases.lovd.nl/shared/genes/EFTUD2).
EFTUD2, MFDM, mandibulofacial dysostosis, mandibulofacial dysostosis Guion-Almeida type, mandibulofacial dysostosis with microcephaly, microcephaly
1059-7794
148-154
Huang, Lijia
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Huang, Lijia
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Vanstone, Megan R.
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Hartley, Taila
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Osmond, Matthew
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Hunter, Alasdair G.W.
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Martinezmoles, Johanna
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Richer, Julie
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van de Kamp, Jiddeke M.
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van Dijk, Fleur S.
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Vandersteen, Anthony M.
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White, Sue M.
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Zou, Ruobing
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Bulman, Dennis E.
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Boycott, Kym M.
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Lines, Matthew A.
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CareRare, Canada
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Huang, Lijia, Vanstone, Megan R. and Hartley, Taila et al. (2016) Mandibulofacial dysostosis with microcephaly: mutation and database update. Human Mutation, 37 (2), 148-154. (doi:10.1002/humu.22924). (PMID:26507355)

Record type: Article

Abstract

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, U5-116kDa / 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 7 microdeletions. Among point mutations, missense substitutions are infrequent (14/76; 18%) relative to stopgain (29/76; 38%), and splicing (33/76; 43%) mutations. Where known, mutation origin was de novo in 48/64 individuals (75%), dominantly-inherited in 12/64 (19%), and due to proven germline mosaicism in 4/64 (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 (http://databases.lovd.nl/shared/genes/EFTUD2).

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More information

Accepted/In Press date: 12 October 2015
e-pub ahead of print date: 28 October 2015
Published date: February 2016
Keywords: EFTUD2, MFDM, mandibulofacial dysostosis, mandibulofacial dysostosis Guion-Almeida type, mandibulofacial dysostosis with microcephaly, microcephaly
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 383502
URI: http://eprints.soton.ac.uk/id/eprint/383502
DOI: doi:10.1002/humu.22924
ISSN: 1059-7794
PURE UUID: 6bcd0386-d020-4dbc-b4ff-6149e06dfbdc
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 17 Nov 2015 13:12
Last modified: 15 Mar 2024 03:00

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Contributors

Author: Lijia Huang
Author: Megan R. Vanstone
Author: Taila Hartley
Author: Matthew Osmond
Author: Nick Barrowman
Author: Judith Allanson
Author: Laura Baker
Author: Tabib A. Dabir
Author: Katrina M. Dipple
Author: William B. Dobyns
Author: Jane Estrella
Author: Hanna Faghfoury
Author: Francine P. Favaro
Author: Himanshu Goel
Author: Pernille A. Gregersen
Author: Karen W. Gripp
Author: Art Grix
Author: Maria-Leine Guion-Almeida
Author: Margaret H. Harr
Author: Cindy Hudson
Author: Alasdair G.W. Hunter
Author: John Johnson
Author: Shelagh K. Joss
Author: Amy Kimball
Author: Usha Kini
Author: Antonie D. Kline
Author: Julie Lauzon
Author: Dorte L. Lildballe
Author: Vanesa López-González
Author: Johanna Martinezmoles
Author: Cliff Meldrum
Author: Ghayda M. Mirzaa
Author: Chantal F. Morel
Author: Jenny E.V. Morton
Author: Louise C. Pyle
Author: Fabiola Quintero-Rivera
Author: Julie Richer
Author: Angela E. Scheuerle
Author: Bitten Schönewolf-Greulich
Author: Deborah J. Shears
Author: Josh Silver
Author: Amanda C. Smith
Author: I. Karen Temple ORCID iD
Author: Jiddeke M. van de Kamp
Author: Fleur S. van Dijk
Author: Anthony M. Vandersteen
Author: Sue M. White
Author: Elaine H. Zackai
Author: Ruobing Zou
Author: Dennis E. Bulman
Author: Kym M. Boycott
Author: Matthew A. Lines
Author: Canada CareRare

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