Haploinsufficiency of a Spliceosomal GTPase Encoded by EFTUD2 Causes Mandibulofacial Dysostosis with Microcephaly

Lines, Matthew A. and Huang, Lijia and Schwartzentruber, Jeremy and Douglas, Stuart L. and Lynch, Danielle C. and Beaulieu, Chandree and Guion-Almeida, Maria Leine and Zechi-Ceide, Roseli Maria and Gener, Blanca and Gillessen-Kaesbach, Gabriele and Nava, Caroline and Baujat, Genevieve and Horn, Denise and Kini, Usha and Caliebe, Almuth and Alanay, Yasemin and Utine, Gulen Eda and Lev, Dorit and Kohlhase, Jurgen and Grix, Arthur W. and Lohmann, Dietmar R. and Hehr, Ute and Boehm, Detlef and Majewski, Jacek and Bulman, Dennis E. and Wieczorek, Dagmar and Boycott, Kym M. (2012) Haploinsufficiency of a Spliceosomal GTPase Encoded by EFTUD2 Causes Mandibulofacial Dysostosis with Microcephaly. AMERICAN JOURNAL OF HUMAN GENETICS, 90 (2). pp. 369-377. ISSN 0002-9297, 1537-6605

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Abstract

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EPTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the fast multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome.

Item Type: Article
Uncontrolled Keywords: DOMINANT RETINITIS-PIGMENTOSA; TREACHER-COLLINS-SYNDROME; RIBOSOMAL TRANSLOCASE; CLEFT-PALATE; RNA; MUTATIONS; PROTEIN; HOMOLOG; SNU114P; GENE;
Subjects: 600 Technology > 610 Medical sciences Medicine
Divisions: Medicine > Lehrstuhl für Humangenetik
Depositing User: Dr. Gernot Deinzer
Date Deposited: 25 May 2020 05:09
Last Modified: 25 May 2020 05:09
URI: https://pred.uni-regensburg.de/id/eprint/19234

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