Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment

Fabiola Ceroni, Nuala H. Simpson, Clyde Francks, Gillian Baird, Gina Conti-Ramsden, Ann Clark, Patrick F. Bolton, Elizabeth R. Hennessy, Peter Donnelly, David R. Bentley, Hilary Martin, Jeremy Parr, Alistair T. Pagnamenta, Elena Maestrini, Elena Bacchelli, Simon E. Fisher, Dianne F. Newbury*, IMGSAC, SLI Consortium, WGS500 Consortium

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

Specific language impairment (SLI), an unexpected failure to develop appropriate language skills despite adequate non-verbal intelligence, is a heterogeneous multifactorial disorder with a complex genetic basis. We identified a homozygous microdeletion of 21,379 bp in the ZNF277 gene (NM_021994.2), encompassing exon 5, in an individual with severe receptive and expressive language impairment. The microdeletion was not found in the proband's affected sister or her brother who had mild language impairment. However, it was inherited from both parents, each of whom carries a heterozygous microdeletion and has a history of language problems. The microdeletion falls within the AUTS1 locus, a region linked to autistic spectrum disorders (ASDs). Moreover, ZNF277 is adjacent to the DOCK4 and IMMP2L genes, which have been implicated in ASD. We screened for the presence of ZNF277 microdeletions in cohorts of children with SLI or ASD and panels of control subjects. ZNF277 microdeletions were at an increased allelic frequency in SLI probands (1.1%) compared with both ASD family members (0.3%) and independent controls (0.4%). We performed quantitative RT-PCR analyses of the expression of IMMP2L, DOCK4 and ZNF277 in individuals carrying either an IMMP2L DOCK4 microdeletion or a ZNF277 microdeletion. Although ZNF277 microdeletions reduce the expression of ZNF277, they do not alter the levels of DOCK4 or IMMP2L transcripts. Conversely, IMMP2L_DOCK4 microdeletions do not affect the expression levels of ZNF277. We postulate that ZNF277 microdeletions may contribute to the risk of language impairments in a manner that is independent of the autism risk loci previously described in this region.

Original languageEnglish
Pages (from-to)1165-1171
Number of pages7
JournalEuropean Journal of Human Genetics
Volume22
Issue number10
DOIs
Publication statusPublished - Oct 2014

Keywords

  • ZNF277
  • SLI
  • language
  • AUTISM SPECTRUM DISORDERS
  • HIDDEN-MARKOV MODEL
  • SNP GENOTYPING DATA
  • CELL SELF-RENEWAL
  • EARLY ADULT LIFE
  • COPY-NUMBER
  • FOLLOW-UP
  • GENOMIC SCREEN
  • CHROMOSOME 7Q
  • MUTATIONS

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