SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.

TitleSPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.
Publication TypeJournal Article
Year of Publication2021
AuthorsRadio, FClementina, Pang, K, Ciolfi, A, Levy, MA, Hernandez-Garcia, A, Pedace, L, Pantaleoni, F, Liu, Z, de Boer, E, Jackson, A, Bruselles, A, McConkey, H, Stellacci, E, Cicero, SLo, Motta, M, Carrozzo, R, Dentici, MLisa, McWalter, K, Desai, M, Monaghan, KG, Telegrafi, A, Philippe, C, Vitobello, A, Au, M, Grand, K, Sanchez-Lara, PA, Baez, J, Lindstrom, K, Kulch, P, Sebastian, J, Madan-Khetarpal, S, Roadhouse, C, MacKenzie, JJ, Monteleone, B, Saunders, CJ, Cuevas, JKJean, Cross, L, Zhou, D, Hartley, T, Sawyer, SL, Monteiro, FPaoli, Secches, TVertemati, Kok, F, Schultz-Rogers, LE, Macke, EL, Morava, E, Klee, EW, Kemppainen, J, Iascone, M, Selicorni, A, Tenconi, R, Amor, DJ, Pais, L, Gallacher, L, Turnpenny, PD, Stals, K, Ellard, S, Cabet, S, Lesca, G, Pascal, J, Steindl, K, Ravid, S, Weiss, K, Castle, AMR, Carter, MT, Kalsner, L, de Vries, BBA, van Bon, BW, Wevers, MR, Pfundt, R, Stegmann, APA, Kerr, B, Kingston, HM, Chandler, KE, Sheehan, W, Elias, AF, Shinde, DN, Towne, MC, Robin, NH, Goodloe, D, Vanderver, A, Sherbini, O, Bluske, K, R Hagelstrom, T, Zanus, C, Faletra, F, Musante, L, Kurtz-Nelson, EC, Earl, RK, Anderlid, B-M, Morin, G, van Slegtenhorst, M, Diderich, KEM, Brooks, AS, Gribnau, J, Boers, RG, Finestra, TRobert, Carter, LB, Rauch, A, Gasparini, P, Boycott, KM, Barakat, TStefan, GrAHm, JM, Faivre, L, Banka, S, Wang, T, Eichler, EE, Priolo, M, Dallapiccola, B, Vissers, LELM, Sadikovic, B, Scott, DA, Holder, JLloyd, Tartaglia, M
JournalAm J Hum Genet
Date Published2021 03 04
KeywordsAdolescent, Autism Spectrum Disorder, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 1, Chromosomes, Human, X, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Female, Haploinsufficiency, Humans, Intellectual Disability, Male, Neurodevelopmental Disorders, Phenotype, RNA-Binding Proteins, Young Adult

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Alternate JournalAm J Hum Genet
PubMed ID33596411
PubMed Central IDPMC8008487
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
R01 HD098458 / HD / NICHD NIH HHS / United States
R01 HG009141 / HG / NHGRI NIH HHS / United States
/ WT / Wellcome Trust / United Kingdom
R01 MH101221 / MH / NIMH NIH HHS / United States