Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Mullegama SV
  • Rosenfeld JA
  • van Bon BW
  • Halbach S
  • Repnikova EA
  • Brick L
  • Li C
  • Dupuis L
  • Aradhya S
  • Stavropoulos DJ
  • Manickam K
  • Mitchell E
  • Hodge JC
  • Talkowski ME
  • Gusella JF
  • Keller K
  • Zonana J
  • Schwartz S
  • Pyatt RE
  • Waggoner DJ
  • Shaffer LG
  • Lin AE
  • de Vries BB
  • Mendoza-Londono R
  • Elsea SH

Grupos

Abstract

Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.

Datos de la publicación

ISSN/ISSNe:
1018-4813, 1476-5438

EUROPEAN JOURNAL OF HUMAN GENETICS  NATURE PUBLISHING GROUP

Tipo:
Article
Páginas:
57-63
Factor de Impacto:
2,004 SCImago
Cuartil:
Q1 SCImago

Citas Recibidas en Web of Science: 33

Documentos

  • No hay documentos

Métricas

Filiaciones mostrar / ocultar

Keywords

  • MBD5; gene dosage; 2q23.1; autism spectrum disorder; microduplication; microdeletion

Proyectos asociados

COMPREHENSIVE, INTEGRATIVE AND GENOMIC APPROACH TO THE UNDERSTANDING AND TREATMENT OF CANCER AND LEUKEMIA.

Investigador Principal: MIGUEL ÁNGEL SANZ ALONSO

PIE13/00046 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2014

Cita

Compartir