Delineation ofEFTUD2Haploinsufficiency-Related Phenotypes Through a Series of 36 Patients

Abstract

Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.

Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome

“…Some of the patients in the non-mutating group were probably misclassified. EFTUD2 was found involved in patients with a CS diagnosis and a specific feature, microcephaly (Lehalle et al, 2014).…”

“…In the literature, the detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90% Jongmans et al, 2006;Zentner, Layman, Martin, & Scacheri, 2010). The elongation factor Tu GTP binding domain-containing 2 (EFTUD2) gene has been involved in some cases (Lehalle et al, 2014).…”

Phenotype analysis of Polish patients with mandibulofacial dysostosis type Guion-Almeida associated with esophageal atresia and choanal atresia caused by EFTUD2 gene mutations

“…Two of our patients had severe microcephaly. According to published reports, occipitofrontal circumference (OFC), even below -4 SD, was described (Lines et al 2012;Luquetti et al 2013;Lehalle et al 2014). Other diagnostic criteria for MFDGA are malar and maxillary hypoplasia, often co-occurring with a cleft palate, choanal and lacrimal atresia, ear anomalies and likewise esophageal atresia (EA) with or without a tracheoesophageal fistula (TEF).…”

“…The full clinical spectrum of MFDGA is heterogeneous (Gordon et al 2012;Lines et al 2012;Wieczorek 2013;Voigt et al 2013;Lehalle et al 2014). However, the phenotype of patients with EFTUD2 mutations is highly variable.…”

Genetics of gastrointestinal atresias

“…MFDGA features include: malar and midface hypoplasia, micrognathia, microcephaly, choanal atresia, cleft palate, microtia, dysplastic ears, hearing loss, intellectual disability, esophageal atresia, congenital heart defects (CDH) and radial ray defects. The presence of limb defects places MFDGA in the AFDs category (preaxial subset), and a reclassification of this syndrome to AFD type Guion-Almeida has been suggested (Driskell et al, 2009;Lehalle et al, 2014;Ozkan et al, 2006;Wieczorek, 2013;Wieczorek et al, 2009). Within the extracraniofacial features present in MFDGA patients CDH and EA are the most frequent (w40%) (Lehalle et al, 2014).…”