Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.

Journal of the European Academy of Dermatology and VenereologyAccepted Articles LETTER TO THE EDITOR Expanding the phenotype of GTF2E2-associated trichothiodystrophy Brian Sperelakis-Beedham, Corresponding Author Brian Sperelakis-Beedham [email protected] orcid.org/0000-0003-2828-460X Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France Correspondence Dr. Brian Sperelakis-Beedham, Robert-Debré University Hospital, 48 Bd Sérurier, 75019 Paris, France. Email address: Email: [email protected]Search for more papers by this authorLyse Ruaud, Lyse Ruaud Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorYoann Vial, Yoann Vial orcid.org/0000-0003-1437-0427 Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorMyriam Rachid, Myriam Rachid Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Neuroscience Department, Human Genetics and Cognitive Function Unit, Pasteur Institute, Paris, FranceSearch for more papers by this authorFaustine Ageorges, Faustine Ageorges Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorLouise Goujon, Louise Goujon Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorAlain Verloes, Alain Verloes Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorAnne-Claude Tabet, Anne-Claude Tabet Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France Neuroscience Department, Human Genetics and Cognitive Function Unit, Pasteur Institute, Paris, FranceSearch for more papers by this authorEmmanuelle Bourrat, Emmanuelle Bourrat Department of Dermatology, Hôpital Saint Louis, AP-HP, Paris, France These authors contributed equally to this paperSearch for more papers by this authorJonathan Lévy, Jonathan Lévy Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France These authors contributed equally to this paperSearch for more papers by this author Brian Sperelakis-Beedham, Corresponding Author Brian Sperelakis-Beedham [email protected] orcid.org/0000-0003-2828-460X Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France Correspondence Dr. Brian Sperelakis-Beedham, Robert-Debré University Hospital, 48 Bd Sérurier, 75019 Paris, France. Email address: Email: [email protected]Search for more papers by this authorLyse Ruaud, Lyse Ruaud Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorYoann Vial, Yoann Vial orcid.org/0000-0003-1437-0427 Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorMyriam Rachid, Myriam Rachid Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Neuroscience Department, Human Genetics and Cognitive Function Unit, Pasteur Institute, Paris, FranceSearch for more papers by this authorFaustine Ageorges, Faustine Ageorges Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorLouise Goujon, Louise Goujon Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorAlain Verloes, Alain Verloes Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorAnne-Claude Tabet, Anne-Claude Tabet Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France Neuroscience Department, Human Genetics and Cognitive Function Unit, Pasteur Institute, Paris, FranceSearch for more papers by this authorEmmanuelle Bourrat, Emmanuelle Bourrat Department of Dermatology, Hôpital Saint Louis, AP-HP, Paris, France These authors contributed equally to this paperSearch for more papers by this authorJonathan Lévy, Jonathan Lévy Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France These authors contributed equally to this paperSearch for more papers by this author First published: 04 October 2023 https://doi.org/10.1111/jdv.19545 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1111/jdv.19545. AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Accepted ArticlesAccepted, unedited articles published online and citable. The final edited and typeset version of record will appear in the future. RelatedInformation

The THOC6 protein is a component of the THO complex. It is involved in mRNA transcription, processing and nuclear export. Interestingly molecular biallelic loss‐of‐function variants of the THOC6 gene were identified in the Beaulieu–Boycott–Innes syndrome (BBIS– OMIM # 613680). This condition was described in 17 patients and is characterized by a moderate to severe intellectual disability, facial dysmorphic features and severe birth defects such as heart, skeletal, ano‐genital and renal congenital malformations.