Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update

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).

Keywords: EFTUD2; MFDM; mandibulofacial dysostosis; mandibulofacial dysostosis Guion-Almeida type; mandibulofacial dysostosis with microcephaly; microcephaly.

Figure 1

Craniofacial morphology in children and adults with mutations in EFTUD2. Panel A: Individual #62 (age 4 months); B: #52 (3.25 years); C: #60 (3.5 years); D: #10a (age 4.5 years); E: #10a (15 years); F: #10b (12 years); G: #57 (age not specified); H: #79a (28 years); I: #79b (25 years); J: #12 (31 years); K: #13 (43 years); L: #34 (47 years). The typical gestalt associated with MFDM (convex facial profile with micrognathia, midface hypoplasia, and sloping forehead, strong supraorbital ridges, high nasal bridge with a prominent ridge and rounded tip, ear anomalies including microtia, dysplastic pinnae, deficient superior helix, posteriorly “squared” earlobes, and/or preauricular tags), while seen in the majority of affected individuals, may occasionally be subtle (e.g., panels F and L).

Figure 2

Growth in MFDM. Primary growth data from 34 previously unpublished affected individuals, and 23 published affected individuals [Lines et al., 2012, Luquetti et al., 2013, Voigt et al., 2013, Sarkar et al., 2015] were modelled using the LMS method, based on a local generalized AIC criterion with smoothing penalty k = 10. The 2nd, 50th, and 98th percentile LMS curves (solid lines) are as shown. Each point represents an individual measurement from an affected individual; dates were corrected for prematurity if applicable. Top: Occipitofrontal circumference (OFC). Shaded area represents sex-averaged general population reference (−2SD to +2SD) [Nellhaus G, 1968]. Bottom: Linear growth versus general sex-averaged general population reference (3rd to 97th centile) from 2014 World Health Organization Growth Charts for Canada (http://www.whogrowthcharts.ca).

Figure 3

All EFTUD2 missense substitutions described to date. (Based on Fabrizio et al., 1997 and Lines et al., 2012). Residues 114–957 of EFTUD2 were modelled on the crystal structure of S. cerevisiae ribosomal elongation factor 2 (eEF2) (PDB: 1N0U). Missense substitutions are distributed throughout all domains of the protein. Conserved motifs identified by Fabrizio et al. (1997), including the GTP-binding domains G1 through G5, and the short conserved domain II motif (∗), are shown. The side chains of His208, Arg262, Lys620, and His856, and Arg938, all basic residues, are predicted to be surface-forming, whereas the sidechains of Gln436, Leu637, Thr678, and Glu829, Gly224, Cys476, Gly499, Gly769, and Ala823 are interior to the model.