Kornelia Neveling

Background: Mutations in EFTUD2 were proven to cause a very distinct mandibulofacial dysostosis type Guion-Almeida (MFDGA, OMIM #610536). Recently, gross deletions and mutations in EFTUD2 were determined to cause syndromic esophageal atresia (EA), as well. We set forth to find further conditions caused by mutations in the EFTUD2 gene (OMIM *603892). Methods and results: We performed exome sequencing in two familial cases with clinical features overlapping with MFDGA and EA, but which were previously assumed to represent distinct entities, a syndrome with esophageal atresia, hypoplasia of zygomatic complex, microcephaly, cup-shaped ears, congenital heart defect, and intellectual disability in a mother and her two children [AJMG 143A(11):1135-1142, 2007] and a supposedly autosomal recessive oto-facial syndrome with midline malformations in two sisters [AJMG 132(4):398-401, 2005]. While the analysis of our exome data was in progress, a recent publication made EFTUD2 mutations highly likely in these families. This hypothesis could be confirmed with exome as well as with Sanger sequencing. Also, in three further sporadic patients, clinically overlapping to these two families, de novo mutations within EFTUD2 were identified by Sanger sequencing. Our clinical and molecular workup of the patients discloses a broad phenotypic spectrum, and describes for the first time an instance of germline mosaicism for an EFTUD2 mutation. Conclusions: The clinical features of the eight patients described here further broaden the phenotypic spectrum caused by EFTUD2 mutations or deletions. We here show, that it not only includes mandibulofacial dysostosis type Guion-Almeida, which should be reclassified as an acrofacial dysostosis because of thumb anomalies (present in 12/35 or 34% of patients) and syndromic esophageal atresia [JMG 49(12). 737-746, 2012], but also the two new syndromes, namely oto-facial syndrome with midline malformations published by Mégarbané et al. [AJMG 132(4): 398-401, 2005] and the syndrome published by Wieczorek et al. [AJMG 143A(11): 1135-1142, 2007] The finding of mild phenotypic features in the mother of one family that could have been overlooked and the possibility of germline mosaicism in apparently healthy parents in the other family should be taken into account when counseling such families.

Zusammenfassung: Neueste Sequenziertechnologien („next-generation sequencing“) erlauben die gleichzeitige Sequenzierung aller proteinkodierender Sequenzen, das sog. Exom. Die Identifizierung der jeweiligen pathogenen Mutation unter den Tausenden detektierten Varianten stellt dabei eine große Herausforderung dar, und neue Strategien für die Priorisierung von Varianten sind unerlässlich. Die jeweilige Wahl einer Strategie ist dabei von verschiedenen Faktoren abhängig, wie z. B. dem Vorhandensein gut charakterisierter Patienten und deren Familien, von der Art der Vererbung, der Schwere der Krankheit sowie deren Frequenz in der allgemeinen Bevölkerung. In dem vorliegenden Übersichtsartikel diskutieren wir die heute gebräuchlichen Strategien zur Identifizierung von neuen Krankheitsgenen mittels Exom-Sequenzierung und beschreiben die Lehren der ersten Exom-Studien. Wir glauben, dass die Sequenzierung von Exomen in den folgenden Jahren die am häufigsten angewandte Methode zur Identifizierung von Krankheitsgenen sein wird und dabei gleichzeitig auch ein großes diagnostisches Potenzial aufweist.