Novel De Novo Splice Site Mutation İn EFNB1 Gene Cause Craniofrontonasal Syndrome

Özgür H., Toksoy G., Altunoğlu U., Kayserili H., Başaran S., Uyguner Z. O.

9th National Medical Genetics Congress of Turkish Medical Society with international Participation, 2010, İstanbul, Turkey, 1 - 05 December 2010, vol.78, no.1, pp.25

  • Publication Type: Conference Paper / Summary Text
  • Volume: 78
  • City: İstanbul
  • Country: Turkey
  • Page Numbers: pp.25
  • Istanbul University Affiliated: Yes


Craniofrontonasal syndrome (CFNS [MIM#304110]) is an Xlinked
disorder paradoxically presenting with greater severity
in heterozygous females than in hemizygous males. Eighty percent
of CFNS cases are caused by mutations in EFNB1 (ephrin
B1) gene located at Xq13.1. Molecular approach to CFNS

patients may be initiated with a screening of the EFNB1 gene
for mutations followed by multiplex ligation-dependent probe
amplification (MLPA) analysis to exclude possible deletion
and duplications in several other genes involved in craniofacial
development – including EFNB1. We report here the molecular
findings of a female patient presenting mild clinical features
of CFNS. Sequence analysis of the EFNB1 gene covering all
the exons, exon–intron boundaries and the previously
described mutation sites presented heterozygous A to G
change in the fourth nucleotide from the five prime site of the
second intron (IVS2+4A>G). There were no other alterations.
Testing of the parents revealed normal sequence, disclosing
de novo occurrence without excluding gonadal mosaicism
in either parent. The change was not observed in any of the 50
control chromosomes. MLPA analysis confirmed the absence
of any duplication or deletions in the genes; FGFR1, FGFR2,
FGFR3, TWIST, MSX2, ALX4, RUNX2. According to Splice
Site Prediction Analysis, IVS2+4A>G abolishes the donor
site. Furthermore, observations of the genomic alignments
with the sequences of the other mammalians shows that the
nucleotide is highly conserved, as comprehensively agreed that
those nucleotides immediately adjacent to splicing donor and
acceptor sites present considerable conservation. Based upon
these findings, we propose that IVS2+4A>G to be a disease
causing mutation in our isolated CFNS case.