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.
| Original language | English |
|---|---|
| Pages (from-to) | 502-516 |
| Number of pages | 15 |
| Journal | American Journal of Human Genetics |
| Volume | 108 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 4 Mar 2021 |
Bibliographical note
Funding Information:The authors thank the participating families and Claudia Nardini (Ospedale Pediatrico Bambino Gesù, Rome) and Serenella Venanzi (Istituto Superiore di Sanità, Rome) for technical assistance. This work was supported, in part, by Fondazione Bambino Gesù (Vite Coraggiose to M.T.), Italian Ministry of Health ( CCR-2017-23669081 and RCR-2020-23670068_001 to M.T.; RF-2018-12366931 to F.C.R. and B.D.; RC 11/16-Institute for Maternal and Child Health IRCCS Burlo Garofolo and RCR-2019-23669117_001 to F.F., L.M., and P.G.), Netherlands Organisation for Scientific Research (ZonMW Veni) (grant 91617021 to T.S.B.), Brain & Behavior Research Foundation (NARSAD Young Investigator Grant to T.S.B.), NIH ( R01HD098458 to D.A.S.), and Genome Canada (Genomic Applications Partnership Program grant to B.S.). Sequencing and data analysis of subject 14 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics and was funded by the National Human Genome Research Institute , National Eye Institute , and National Heart, Lung, and Blood Institute ( UM1 HG008900 ) and by the National Human Genome Research Institute ( R01 HG009141 ). Sequencing and data analyses of subjects 33 and 34 were supported by the NIH ( R01MH101221 to E.E.E.) and Simons Foundation ( SFARI #608045 to E.E.E.). The Deciphering Developmental Disorders (DDD) study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009–003 ). This study makes use of DECIPHER, which is funded by the Wellcome. This work has been carried out in the frame of the ERN-ITHACA research activities.
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© 2021 American Society of Human Genetics
