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Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.
Hum Mutat. 2016 Feb; 37(2):148-54.HM

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, U5-116 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 stop-gain (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 (http://databases.lovd.nl/shared/genes/EFTUD2).

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Authors+Show Affiliations

Huang L
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Vanstone MR
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Hartley T
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Osmond M
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Barrowman N
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada. Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.
Allanson J
Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada. Department of Genetics, The Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Baker L
Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Dabir TA
Clinical Genetics Department, Belfast City Hospital, Belfast, UK.
Dipple KM
Department of Pediatrics and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California.
Dobyns WB
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
Estrella J
Department of Medical Genetics, Westmead Hospital, Sydney, Australia.
Faghfoury H
The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Favaro FP
Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, Brazil.
Goel H
Hunter Genetics, Newcastle, Waratah, Australia. University of Newcastle, Newcastle - School of Medicine and Public Health, Faculty of Health, Callaghan, Australia.
Gregersen PA
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Gripp KW
Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Grix A
Department of Genetics, Permanente Medical Group, Roseville, California.
Guion-Almeida ML
Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, Brazil.
Harr MH
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania.
Hudson C
Shodair Children's Hospital, Helena, Montana.
Hunter AG
Medical Geneticist, Ottawa, Ontario, Canada.
Johnson J
Shodair Children's Hospital, Helena, Montana. Clinical Genetics and Metabolism, Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts.
Joss SK
West of Scotland Clinical Genetics Service, South Glasgow University Hospital, Glasgow, UK.
Kimball A
Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, Maryland.
Kini U
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
Kline AD
Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, Maryland.
Lauzon J
Department of Medical Genetics, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
Lildballe DL
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
López-González V
Sección de Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain. Grupo Clínico Vinculado al Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Martinezmoles J
Department of Genetics, Sacramento Medical Center, Sacramento, California.
Meldrum C
NSW Health Pathology, Newcastle, Australia.
Mirzaa GM
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
Morel CF
The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Morton JE
West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham, UK.
Pyle LC
Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Quintero-Rivera F
Department of Pathology and Laboratory Medicine, UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, California.
Richer J
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada. Department of Genetics, The Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Scheuerle AE
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
Schönewolf-Greulich B
Genetic Counselling Clinic Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
Shears DJ
Oxford Regional Genetics Service, The Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.
Silver J
The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Smith AC
Department of Genetics, The Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Temple IK
Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK. Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
UCLA Clinical Genomics Center
No affiliation info available
van de Kamp JM
Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands.
van Dijk FS
Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands.
Vandersteen AM
Maritime Medical Genetics Service, IWKHealth Centre, Halifax, Nova Scotia, Canada.
White SM
Victoria Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, Australia. Department of Paediatrics, University of Melbourne, Melbourne, Australia.
Zackai EH
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Zou R
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Care4Rare Canada Consortium
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Bulman DE
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada. Newborn Screening Ontario, The Children's Hospital of Eastern Ontario, Ottawa, Canada.
Boycott KM
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada. Department of Genetics, The Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Lines MA
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada. Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada. Metabolics and Newborn Screening, Department of Pediatrics, The Children's Hospital of Eastern Ontario, Ottawa, Canada.

MeSH

Abnormalities, MultipleAmino Acid MotifsDatabases, GeneticGene ExpressionHaploinsufficiencyHearing LossHumansIntellectual DisabilityMandibulofacial DysostosisMicrocephalyModels, MolecularMolecular Sequence DataMutationPenetrancePeptide Elongation FactorsPhenotypeProtein Structure, SecondaryProtein Structure, TertiaryRNA SplicingRibonucleoprotein, U5 Small NuclearSpliceosomes

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

26507355

Citation

Huang, Lijia, et al. "Mandibulofacial Dysostosis With Microcephaly: Mutation and Database Update." Human Mutation, vol. 37, no. 2, 2016, pp. 148-54.
Huang L, Vanstone MR, Hartley T, et al. Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update. Hum Mutat. 2016;37(2):148-54.
Huang, L., Vanstone, M. R., Hartley, T., Osmond, M., Barrowman, N., Allanson, J., Baker, L., Dabir, T. A., Dipple, K. M., Dobyns, W. B., Estrella, J., Faghfoury, H., Favaro, F. P., Goel, H., Gregersen, P. A., Gripp, K. W., Grix, A., Guion-Almeida, M. L., Harr, M. H., ... Lines, M. A. (2016). Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update. Human Mutation, 37(2), 148-54. https://doi.org/10.1002/humu.22924
Huang L, et al. Mandibulofacial Dysostosis With Microcephaly: Mutation and Database Update. Hum Mutat. 2016;37(2):148-54. PubMed PMID: 26507355.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update. AU - Huang,Lijia, AU - Vanstone,Megan R, AU - Hartley,Taila, AU - Osmond,Matthew, AU - Barrowman,Nick, AU - Allanson,Judith, AU - Baker,Laura, AU - Dabir,Tabib A, AU - Dipple,Katrina M, AU - Dobyns,William B, AU - Estrella,Jane, AU - Faghfoury,Hanna, AU - Favaro,Francine P, AU - Goel,Himanshu, AU - Gregersen,Pernille A, AU - Gripp,Karen W, AU - Grix,Art, AU - Guion-Almeida,Maria-Leine, AU - Harr,Margaret H, AU - Hudson,Cindy, AU - Hunter,Alasdair G W, AU - Johnson,John, AU - Joss,Shelagh K, AU - Kimball,Amy, AU - Kini,Usha, AU - Kline,Antonie D, AU - Lauzon,Julie, AU - Lildballe,Dorte L, AU - López-González,Vanesa, AU - Martinezmoles,Johanna, AU - Meldrum,Cliff, AU - Mirzaa,Ghayda M, AU - Morel,Chantal F, AU - Morton,Jenny E V, AU - Pyle,Louise C, AU - Quintero-Rivera,Fabiola, AU - Richer,Julie, AU - Scheuerle,Angela E, AU - Schönewolf-Greulich,Bitten, AU - Shears,Deborah J, AU - Silver,Josh, AU - Smith,Amanda C, AU - Temple,I Karen, AU - ,, AU - van de Kamp,Jiddeke M, AU - van Dijk,Fleur S, AU - Vandersteen,Anthony M, AU - White,Sue M, AU - Zackai,Elaine H, AU - Zou,Ruobing, AU - ,, AU - Bulman,Dennis E, AU - Boycott,Kym M, AU - Lines,Matthew A, Y1 - 2015/11/19/ PY - 2015/07/08/received PY - 2015/10/12/accepted PY - 2015/10/29/entrez PY - 2015/10/29/pubmed PY - 2016/10/19/medline KW - EFTUD2 KW - MFDM KW - mandibulofacial dysostosis KW - mandibulofacial dysostosis Guion-Almeida type KW - mandibulofacial dysostosis with microcephaly KW - microcephaly SP - 148 EP - 54 JF - Human mutation JO - Hum Mutat VL - 37 IS - 2 N2 - 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 stop-gain (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 (http://databases.lovd.nl/shared/genes/EFTUD2). SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/26507355/Mandibulofacial_Dysostosis_with_Microcephaly:_Mutation_and_Database_Update_ DB - PRIME DP - Unbound Medicine ER -