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, U5-116 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).
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Lijia
L
Huang
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Megan R
MR
Vanstone
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Taila
T
Hartley
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Matthew
M
Osmond
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.|Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.
Nick
N
Barrowman
Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.|Department of Genetics, The Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Judith
J
Allanson
Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Laura
L
Baker
Clinical Genetics Department, Belfast City Hospital, Belfast, UK.
Tabib A
TA
Dabir
Department of Pediatrics and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California.
Katrina M
KM
Dipple
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.|Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
William B
WB
Dobyns
Department of Medical Genetics, Westmead Hospital, Sydney, Australia.
Jane
J
Estrella
The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Hanna
H
Faghfoury
Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, Brazil.
Francine P
FP
Favaro
Hunter Genetics, Newcastle, Waratah, Australia.|University of Newcastle, Newcastle - School of Medicine and Public Health, Faculty of Health, Callaghan, Australia.
Himanshu
H
Goel
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Pernille A
PA
Gregersen
Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Karen W
KW
Gripp
Department of Genetics, Permanente Medical Group, Roseville, California.
Art
A
Grix
Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, Brazil.
Maria-Leine
ML
Guion-Almeida
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania.
Margaret H
MH
Harr
Shodair Children's Hospital, Helena, Montana.
Cindy
C
Hudson
Medical Geneticist, Ottawa, Ontario, Canada.
Alasdair G W
AG
Hunter
Shodair Children's Hospital, Helena, Montana.|Clinical Genetics and Metabolism, Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts.
John
J
Johnson
West of Scotland Clinical Genetics Service, South Glasgow University Hospital, Glasgow, UK.
Shelagh K
SK
Joss
Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, Maryland.
Amy
A
Kimball
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
Usha
U
Kini
Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, Maryland.
Antonie D
AD
Kline
Department of Medical Genetics, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
Julie
J
Lauzon
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Dorte L
DL
Lildballe
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.
Vanesa
V
López-González
Department of Genetics, Sacramento Medical Center, Sacramento, California.
Johanna
J
Martinezmoles
NSW Health Pathology, Newcastle, Australia.
Cliff
C
Meldrum
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.|Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
Ghayda M
GM
Mirzaa
The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Chantal F
CF
Morel
West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham, UK.
Jenny E V
JE
Morton
Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Louise C
LC
Pyle
Department of Pathology and Laboratory Medicine, UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, California.
Fabiola
F
Quintero-Rivera
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.
Julie
J
Richer
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
Angela E
AE
Scheuerle
Genetic Counselling Clinic Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
Bitten
B
Schönewolf-Greulich
Oxford Regional Genetics Service, The Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.
Deborah J
DJ
Shears
The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Josh
J
Silver
Department of Genetics, The Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Amanda C
AC
Smith
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.
I Karen
IK
Temple
Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands.
Jiddeke M
JM
van de Kamp
Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands.
Fleur S
FS
van Dijk
Maritime Medical Genetics Service, IWKHealth Centre, Halifax, Nova Scotia, Canada.
Anthony M
AM
Vandersteen
Victoria Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, Australia.
Sue M
SM
White
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Elaine H
EH
Zackai
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Ruobing
R
Zou
The Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
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.
Dennis E
DE
Bulman
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.
Kym M
KM
Boycott
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.
Matthew A
MA
Lines
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D020816:Amino Acid Motifs; D030541:Databases, Genetic; D015870:Gene Expression; D057895:Haploinsufficiency; D034381:Hearing Loss / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008342:Mandibulofacial Dysostosis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019683:Penetrance; D010445:Peptide Elongation Factors / Q000235:genetics*; D010641:Phenotype; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012326:RNA Splicing; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000235:genetics*; D017381:Spliceosomes / Q000235:genetics
C581608:EFTUD2 protein, human; D010445:Peptide Elongation Factors; D017415:Ribonucleoprotein, U5 Small Nuclear
EFTUD2; MFDM; mandibulofacial dysostosis; mandibulofacial dysostosis Guion-Almeida type; mandibulofacial dysostosis with microcephaly; microcephaly