SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.
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- Authors:
- Radio FC
Pang K
Ciolfi A
Levy MA
Hernández-García A
Pedace L
Pantaleoni F
Liu Z
de Boer E
Jackson A
Bruselles A
McConkey H
Stellacci E
Lo Cicero S
Motta M
Carrozzo R
Dentici ML
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
Jean Cuevas JK
Cross L
Zhou D
Hartley T
Sawyer SL
Monteiro FP
Secches TV
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
Hagelstrom RT
Zanus C
Faletra F
Musante L
Kurtz-Nelson EC
Earl RK
Anderlid BM
Morin G
van Slegtenhorst M
Diderich KEM
Brooks AS
Gribnau J
Boers RG
Finestra TR
Carter LB
Rauch A
Gasparini P
Boycott KM
Barakat TS
Graham JM Jr
Faivre L
Banka S
Wang T
Eichler EE
Priolo M
Dallapiccola B
Vissers LELM
Sadikovic B
Scott DA
Holder JL Jr
Tartaglia M - Source:
-
American journal of human genetics [Am J Hum Genet] 2021 Mar 04; Vol. 108 (3), pp. 502-516. Date of Electronic Publication: 2021 Feb 16. - Publication Date:
- 2021-03-04
- Language:
- English
- 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.
(Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.) - Subjects:
- Adolescent
Autism Spectrum Disorder genetics
Autism Spectrum Disorder pathology
Child
Child, Preschool
Chromosome Deletion
Chromosome Disorders physiopathology
DNA Methylation genetics
Epigenesis, Genetic genetics
Female
Haploinsufficiency genetics
Humans
Intellectual Disability genetics
Intellectual Disability physiopathology
Male
Neurodevelopmental Disorders genetics
Neurodevelopmental Disorders physiopathology
Phenotype
Young Adult
Chromosome Disorders genetics
Chromosomes, Human, Pair 1 genetics
Chromosomes, Human, X genetics
DNA-Binding Proteins genetics
RNA-Binding Proteins genetics - Format:
- Academic Journal
- DOI:
- 10.1016/j.ajhg.2021.01.015
- Database:
- MEDLINE
- Journal:
- American journal of human genetics
- Volume:
- 108
- Issue:
- 3
- Page Start:
- 502
- ISSN:
- 1537-6605
