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

ABSTRACT: 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.

SUBMITTER: Radio FC

PROVIDER: S-EPMC8008487 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Radio Francesca Clementina FC Pang Kaifang K Ciolfi Andrea A Levy Michael A MA Hernández-García Andrés A Pedace Lucia L Pantaleoni Francesca F Liu Zhandong Z de Boer Elke E Jackson Adam A Bruselles Alessandro A McConkey Haley H Stellacci Emilia E Lo Cicero Stefania S Motta Marialetizia M Carrozzo Rosalba R Dentici Maria Lisa ML McWalter Kirsty K Desai Megha M Monaghan Kristin G KG Telegrafi Aida A Philippe Christophe C Vitobello Antonio A Au Margaret M Grand Katheryn K Sanchez-Lara Pedro A PA Baez Joanne J Lindstrom Kristin K Kulch Peggy P Sebastian Jessica J Madan-Khetarpal Suneeta S Roadhouse Chelsea C MacKenzie Jennifer J JJ Monteleone Berrin B Saunders Carol J CJ Jean Cuevas July K JK Cross Laura L Zhou Dihong D Hartley Taila T Sawyer Sarah L SL Monteiro Fabíola Paoli FP Secches Tania Vertemati TV Kok Fernando F Schultz-Rogers Laura E LE Macke Erica L EL Morava Eva E Klee Eric W EW Kemppainen Jennifer J Iascone Maria M Selicorni Angelo A Tenconi Romano R Amor David J DJ Pais Lynn L Gallacher Lyndon L Turnpenny Peter D PD Stals Karen K Ellard Sian S Cabet Sara S Lesca Gaetan G Pascal Joset J Steindl Katharina K Ravid Sarit S Weiss Karin K Castle Alison M R AMR Carter Melissa T MT Kalsner Louisa L de Vries Bert B A BBA van Bon Bregje W BW Wevers Marijke R MR Pfundt Rolph R Stegmann Alexander P A APA Kerr Bronwyn B Kingston Helen M HM Chandler Kate E KE Sheehan Willow W Elias Abdallah F AF Shinde Deepali N DN Towne Meghan C MC Robin Nathaniel H NH Goodloe Dana D Vanderver Adeline A Sherbini Omar O Bluske Krista K Hagelstrom R Tanner RT Zanus Caterina C Faletra Flavio F Musante Luciana L Kurtz-Nelson Evangeline C EC Earl Rachel K RK Anderlid Britt-Marie BM Morin Gilles G van Slegtenhorst Marjon M Diderich Karin E M KEM Brooks Alice S AS Gribnau Joost J Boers Ruben G RG Finestra Teresa Robert TR Carter Lauren B LB Rauch Anita A Gasparini Paolo P Boycott Kym M KM Barakat Tahsin Stefan TS Graham John M JM Faivre Laurence L Banka Siddharth S Wang Tianyun T Eichler Evan E EE Priolo Manuela M Dallapiccola Bruno B Vissers Lisenka E L M LELM Sadikovic Bekim B Scott Daryl A DA Holder Jimmy Lloyd JL Tartaglia Marco M

American journal of human genetics 20210216 3

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 ...[more]

PMID: 33596411

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Project description:BackgroundHaploinsufficient (HI) genes are those for which a reduction in copy number in a diploid from two to one results in significantly reduced fitness. Haploinsufficiency is increasingly implicated in human disease, and so predicting this phenotype could provide insights into the genetic mechanisms behind many human diseases, including some cancers.ResultsIn the present work we show that orthologues of Saccharomyces cerevisiae HI genes are preferentially retained across the kingdom Fungi, and that the HI genes of S. cerevisiae can be used to predict haploinsufficiency in humans. Our HI gene predictions confirm known associations between haploinsufficiency and genetic disease, and predict several further disorders in which the phenotype may be relevant. Haploinsufficiency is also clearly relevant to the gene-dosage imbalances inherent in eukaryotic sex-determination systems. In S. cerevisiae, HI genes are over-represented on chromosome III, the chromosome that determines yeast's mating type. This may be a device to select against the loss of one copy of chromosome III from a diploid. We found that orthologues of S. cerevisiae HI genes are also over-represented on the mating-type chromosomes of other yeasts and filamentous fungi. In animals with heterogametic sex determination, accumulation of HI genes on the sex chromosomes would compromise fitness in both sexes, given X chromosome inactivation in females. We found that orthologues of S. cerevisiae HI genes are significantly under-represented on the X chromosomes of mammals and of Caenorhabditis elegans. There is no X inactivation in Drosophila melanogaster (increased expression of X in the male is used instead) and, in this species, we found no depletion of orthologues to yeast HI genes on the sex chromosomes.ConclusionA special relationship between HI genes and the sex/mating-type chromosome extends from S. cerevisiae to Homo sapiens, with the microbe being a useful model for species throughout the evolutionary range. Furthermore, haploinsufficiency in yeast can predict the phenotype in higher organisms.

Dataset Information

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

Publications

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

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