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

Śmigiel, Robert; Bezniakow, Natalia; Jakubiak, Aleksandra; Błoch, Michał; Patkowski, Dariusz; Obersztyn, Ewa; Sasiadek, Maria M.

doi:10.1007/s13353-014-0255-4

Cited by 20 publications

(19 citation statements)

References 11 publications

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“…). A fifth mutation, p.(Arg262Trp), is a recurrent mutation of a conserved residue in EFTUD2's GTP‐binding site observed in three unrelated families [Lines et al., ; Smigiel et al., ; this study]. The remaining nine missense substitutions, which are predicted to be interior to EFTUD2, could conceivably affect protein stability by any of several mechanisms, including effects on: protein stability, conformation, localization, and/or post‐translational modifications.…”

Section: Biological Relevancementioning

confidence: 78%

“…Previous to this report, the literature includes 69 individuals (64 kindreds) with mutations of EFTUD2 (NM_004247.3), excluding individuals with cytogenetically visible chromosomal aberrations [Lines et al., ; Gordon et al., ; Need et al., ; Bernier et al., ; Luquetti et al., ; Voigt et al., ; Lehalle et al., ; Gandomi et al., ; Smigiel et al., ; Sarkar et al., ; Vincent et al., ]. Here, we summarize all published affected individuals and present genotypic and phenotypic data from a further 38 affected individuals belonging to 30 kindreds (Supp.…”

Section: Variantsmentioning

confidence: 99%

“…To better define the spectrum of EFTUD2 ‐associated clinical symptoms, we reviewed the clinical features of all newly reported individuals in this study (Supp. Table S2), and tabulated the feature‐specific penetrance of each of the major clinical findings across the entire cohort of all known affected individuals (Table ) [Lines et al., ; Need et al., ; Bernier et al., ; Gordon et al., ; Voigt et al., ; Luquetti et al., ; Lehalle et al., , Smigiel et al., ]. Highly penetrant features seen in >80% of individuals include developmental delay, microcephaly (here defined as occipitofrontal circumference (OFC) two or more standard deviations below mean), micrognathia, malar hypoplasia, small or dysplastic pinnae, and hearing loss (typically conductive, but occasionally sensorineural or mixed).…”

Section: Clinical Relevancementioning

confidence: 99%

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Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update

Huang¹,

Vanstone²,

Hartley³

et al. 2015

Human Mutation

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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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Section: Biological Relevancementioning

confidence: 78%

Section: Variantsmentioning

confidence: 99%

Section: Clinical Relevancementioning

confidence: 99%

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Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update

Huang¹,

Vanstone²,

Hartley³

et al. 2015

Human Mutation

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“…In 2012, mutations in EFTUD2 were identified via exome sequencing as the cause of MFDGA (8), and to date, more than 50 probands with EFTUD2 loss-offunction mutations or deletions have been described (5,8,(37)(38)(39)(40)(41)(42)(43)(44). Major features of MFDGA are MFD, external ear malformations, microcephaly and intellectual disability, while less frequent features include hearing loss, cleft palate, choanal atresia, oesophageal atresia, congenital heart defects and radial ray defects (Table 1).…”

Section: Mandibulofacial Dysostosis Guion-almeida Typementioning

confidence: 99%

A review of craniofacial disorders caused by spliceosomal defects

et al. 2015

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The spliceosome is a large ribonucleoprotein complex that removes introns from pre-mRNA transcripts. Mutations in EFTUD2, encoding a component of the major spliceosome, have recently been identified as the cause of mandibulofacial dysostosis, Guion-Almeida type (MFDGA), characterized by mandibulofacial dysostosis, microcephaly, external ear malformations and intellectual disability. Mutations in several other genes involved in spliceosomal function or linked aspects of mRNA processing have also recently been identified in human disorders with specific craniofacial malformations: SF3B4 in Nager syndrome, an acrofacial dysostosis (AFD); SNRPB in cerebrocostomandibular syndrome, characterized by Robin sequence and rib defects; EIF4A3 in the AFD Richieri-Costa-Pereira syndrome, characterized by Robin sequence, median mandibular cleft and limb defects; and TXNL4A in Burn-McKeown syndrome, involving specific craniofacial dysmorphisms. Here, we review phenotypic and molecular aspects of these syndromes. Given the apparent sensitivity of craniofacial development to defects in mRNA processing, it is possible that mutations in other proteins involved in spliceosomal function will emerge in the future as causative for related human disorders.

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“…In most of these craniofacial disorders, the disease variants inactivate one allele and are proposed to cause disease through haploinsufficiency. Patients with MFDGA possess a wide variety of variants within EFTUD2 that potentially inactivate one EFTUD2 allele (Gordon et al, 2012;Huang et al, 2016;Lacour et al, 2019;Lehalle et al, 2014;Lines et al, 2012;Luquetti et al, 2013;Matsuo et al, 2017;Sarkar et al, 2015;Smigiel et al, 2015;Vincent et al, 2016;Voigt et al, 2013). EFTUD2/Snu114 is a GTPase, and a core U5 snRNP protein that is present throughout the splicing cycle and regulates spliceosome remodeling (Frazer, Nancollis, & O'Keefe, 2008).…”

Section: Introductionmentioning

confidence: 99%

EFTUD2 missense variants disrupt protein function and splicing in mandibulofacial dysostosis Guion‐Almeida type

et al. 2020

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Pathogenic variants in the core spliceosome U5 small nuclear ribonucleoprotein gene EFTUD2/SNU114 cause the craniofacial disorder mandibulofacial dysostosis Guion‐Almeida type (MFDGA). MFDGA‐associated variants in EFTUD2 comprise large deletions encompassing EFTUD2, intragenic deletions and single nucleotide truncating or missense variants. These variants are predicted to result in haploinsufficiency by loss‐of‐function of the variant allele. While the contribution of deletions within EFTUD2 to allele loss‐of‐function are self‐evident, the mechanisms by which missense variants are disease‐causing have not been characterized functionally. Combining bioinformatics software prediction, yeast functional growth assays, and a minigene (MG) splicing assay, we have characterized how MFDGA missense variants result in EFTUD2 loss‐of‐function. Only four of 19 assessed missense variants cause EFTUD2 loss‐of‐function through altered protein function when modeled in yeast. Of the remaining 15 missense variants, five altered the normal splicing pattern of EFTUD2 pre‐messenger RNA predominantly through exon skipping or cryptic splice site activation, leading to the introduction of a premature termination codon. Comparison of bioinformatic predictors for each missense variant revealed a disparity amongst different software packages and, in many cases, an inability to correctly predict changes in splicing subsequently determined by MG interrogation. This study highlights the need for laboratory‐based validation of bioinformatic predictions for EFTUD2 missense variants.

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

Cited by 20 publications

References 11 publications

Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update

Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update

A review of craniofacial disorders caused by spliceosomal defects

EFTUD2 missense variants disrupt protein function and splicing in mandibulofacial dysostosis Guion‐Almeida type

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