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).

Huang L ，Vanstone MR ，Hartley T ，Osmond M ，Barrowman N ，Allanson J ，Baker L ，Dabir TA ，Dipple KM ，Dobyns WB ，Estrella J ，Faghfoury H ，Favaro FP ，Goel H ，Gregersen PA ，Gripp KW ，Grix A ，Guion-Almeida ML ，Harr MH ，Hudson C ，Hunter AG ，Johnson J ，Joss SK ，Kimball A ，Kini U ，Kline AD ，Lauzon J ，Lildballe DL ，López-González V ，Martinezmoles J ，Meldrum C ，Mirzaa GM ，Morel CF ，Morton JE ，Pyle LC ，Quintero-Rivera F ，Richer J ，Scheuerle AE ，Schönewolf-Greulich B ，Shears DJ ，Silver J ，Smith AC ，Temple IK ，UCLA Clinical Genomics Center ，van de Kamp JM ，van Dijk FS ，Vandersteen AM ，White SM ，Zackai EH ，Zou R ，Care4Rare Canada Consortium ，Bulman DE ，Boycott KM ，Lines MA ... -  《-》

Delineation of EFTUD2 haploinsufficiency-related phenotypes through a series of 36 patients.

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.

Lehalle D ，Gordon CT ，Oufadem M ，Goudefroye G ，Boutaud L ，Alessandri JL ，Baena N ，Baujat G ，Baumann C ，Boute-Benejean O ，Caumes R ，Decaestecker C ，Gaillard D ，Goldenberg A ，Gonzales M ，Holder-Espinasse M ，Jacquemont ML ，Lacombe D ，Manouvrier-Hanu S ，Marlin S ，Mathieu-Dramard M ，Morin G ，Pasquier L ，Petit F ，Rio M ，Smigiel R ，Thauvin-Robinet C ，Vasiljevic A ，Verloes A ，Malan V ，Munnich A ，de Pontual L ，Vekemans M ，Lyonnet S ，Attié-Bitach T ，Amiel J ... -  《-》

Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly.

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 EFTUD2-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 first 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.

Lines MA ，Huang L ，Schwartzentruber J ，Douglas SL ，Lynch DC ，Beaulieu C ，Guion-Almeida ML ，Zechi-Ceide RM ，Gener B ，Gillessen-Kaesbach G ，Nava C ，Baujat G ，Horn D ，Kini U ，Caliebe A ，Alanay Y ，Utine GE ，Lev D ，Kohlhase J ，Grix AW ，Lohmann DR ，Hehr U ，Böhm D ，FORGE Canada Consortium ，Majewski J ，Bulman DE ，Wieczorek D ，Boycott KM ... -  《-》

Mandibulofacial dysostosis with microcephaly: An expansion of the phenotype via parental survey.

Mandibulofacial dysostosis with microcephaly (MFDM) is due to haploinsufficiency of spliceosomal GTPase EFTUD2. Features include microcephaly, craniofacial dysmorphology, developmental disability, and other anomalies. We surveyed parents of individuals with MFDM to expand knowledge about health, development, and parental concerns. Participants included attendees of the inaugural MFDM family conference in June 2019 and members of the MFDM online group. To explore MFDM variable expressivity, we offered targeted Sanger sequencing for untested parents. Forty-seven parents participated in the survey. 59% of individuals with MFDM were male, with mean age 6.4 years (range 8 months to 49 years). Similar to the literature (n = 123), common features include microcephaly, cleft palate, choanal stenosis, tracheoesophageal fistula, heart problems, and seizures. New information includes airway intervention details, age-based developmental outcomes, rate of vision refractive errors, and lower incidences of prematurity and IUGR. Family concerns focused on development, communication, and increased support. Targeted Sanger sequencing for families of seven individuals demonstrated de novo variants, for a total of 91.9% de novo EFTUD2 variants (n = 34/37). This study reports the largest single cohort of individuals with MFDM, expands phenotypic spectrum and inheritance patterns, improves understanding of developmental outcomes and care needs, and identifies development as the biggest concern for parents.

Abell K ，Hopkin RJ ，Bender PL ，Jackson F ，Smallwood K ，Sullivan B ，Stottmann RW ，Saal HM ，Weaver KN ... -  《-》

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

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.

Thomas HB ，Wood KA ，Buczek WA ，Gordon CT ，Pingault V ，Attié-Bitach T ，Hentges KE ，Varghese VC ，Amiel J ，Newman WG ，O'Keefe RT ... -  《-》