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


Francesca Clementina Radio
Kaifang Pang
Andrea Ciolfi
Michael A. Levy
Andrés Hernández-García
Lucia Pedace
Francesca Pantaleoni
Zhandong Liu
Elke de Boer
Adam Jackson
Alessandro Bruselles
Haley McConkey
Emilia Stellacci
Stefania Lo Cicero
Marialetizia Motta
Rosalba Carrozzo
Maria Lisa Dentici
Kirsty McWalter
Megha Desai
Kristin G. Monaghan
Aida Telegrafi
Christophe Philippe
Antonio Vitobello
Margaret Au
Katheryn Grand
Pedro A. Sanchez-Lara
Joanne Baez
Kristin Lindstrom
Peggy Kulch
Jessica Sebastian
Suneeta Madan-Khetarpal
Chelsea Roadhouse
Jennifer J. MacKenzie
Berrin Monteleone
Carol J. Saunders, Children's Mercy HospitalFollow
July K. Jean Cuevas, Children's Mercy HospitalFollow
Laura A. Cross, Children's Mercy HospitalFollow
Dihong Zhou, Children's Mercy HospitalFollow
Taila Hartley
Sarah L. Sawyer
Fabíola Paoli Monteiro
Tania Vertemati Secches
Fernando Kok
Laura E. Schultz-Rogers
Erica L. Macke
Eva Morava
Eric W. Klee
Jennifer Kemppainen
Maria Iascone
Angelo Selicorni
Romano Tenconi
David J. Amor
Lynn Pais
Lyndon Gallacher
Peter D. Turnpenny
Karen Stals
Sian Ellard
Sara Cabet
Gaetan Lesca
Joset Pascal
Katharina Steindl
Sarit Ravid
Karin Weiss
Alison M R Castle
Melissa T. Carter
Louisa Kalsner
Bert B A de Vries
Bregje W. van Bon
Marijke R. Wevers
Rolph Pfundt
Alexander P A Stegmann
Bronwyn Kerr
Helen M. Kingston
Kate E. Chandler
Willow Sheehan
Abdallah F. Elias
Deepali N. Shinde
Meghan C. Towne
Nathaniel H. Robin
Dana Goodloe
Adeline Vanderver
Omar Sherbini
Krista Bluske
R Tanner Hagelstrom
Caterina Zanus
Flavio Faletra
Luciana Musante
Evangeline C. Kurtz-Nelson
Rachel K. Earl
Britt-Marie Anderlid
Gilles Morin
Marjon van Slegtenhorst
Karin E M Diderich
Alice S. Brooks
Joost Gribnau
Ruben G. Boers
Teresa Robert Finestra
Lauren B. Carter
Anita Rauch
Paolo Gasparini
Kym M. Boycott
Tahsin Stefan Barakat
John M. Graham
Laurence Faivre
Siddharth Banka
Tianyun Wang
Evan E. Eichler
Manuela Priolo
Bruno Dallapiccola
Lisenka E L M Vissers
Bekim Sadikovic
Daryl A. Scott
Jimmy Lloyd Holder
Marco Tartaglia

Document Type


Publication Date



DOI: 10.1016/j.ajhg.2021.01.015


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.

Journal Title

American journal of human genetics





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Last Page


MeSH Keywords

Adolescent; 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


1p36; DNA methylome analysis; SPEN; X chromosome; distal 1p36 deletion syndrome; episignature; genotype-phenotype correlations; neurodevelopmental disorder; obesity; proximal 1p36 deletion syndrome

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