X-Linked Deafness-2 (DFNX2) Phenotype Associated With a Paracentric Inversion Upstream of POU3F4 Purpose The authors report on a 7-year-old male, designated FR, who has severe sensorineural hearing loss. Features include a round face, hypertelorism, epicanthal folds, and flat nasal root. Although there were early developmental concerns regarding FR, all but his speech delay resolved when he was placed in an educational program ... Clinical Focus
Clinical Focus  |   March 01, 2014
X-Linked Deafness-2 (DFNX2) Phenotype Associated With a Paracentric Inversion Upstream of POU3F4
 
Author Affiliations & Notes
  • Gregory J. Anger
    Queen’s University, Ontario, Canada
    Kingston General Hospital, Ontario, Canada
  • Susan Crocker
    Queen’s University, Ontario, Canada
    Kingston General Hospital, Ontario, Canada
  • Kyle McKenzie
    Kingston General Hospital, Ontario, Canada
  • Kerry K. Brown
    Harvard Medical School, Harvard University, Boston, MA
    Brigham and Women’s Hospital, Boston, MA
  • Cynthia C. Morton
    Harvard Medical School, Harvard University, Boston, MA
    Brigham and Women’s Hospital, Boston, MA
  • Karen Harrison
    IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada
  • Jennifer J. MacKenzie
    Queen’s University, Ontario, Canada
    Kingston General Hospital, Ontario, Canada
  • Disclosure:The authors have declared that no competing interests existed at the time of publication.
    Disclosure:The authors have declared that no competing interests existed at the time of publication.×
  • Correspondence to Greg Anger: greg.anger@gmail.com
  • Editor: Larry Humes
    Editor: Larry Humes×
Article Information
Hearing Disorders / Special Populations / Genetic & Congenital Disorders / Clinical Focus
Clinical Focus   |   March 01, 2014
X-Linked Deafness-2 (DFNX2) Phenotype Associated With a Paracentric Inversion Upstream of POU3F4
American Journal of Audiology, March 2014, Vol. 23, 1-6. doi:10.1044/1059-0889(2013/13-0018)
History: Received March 25, 2012 , Revised August 13, 2013 , Accepted September 2, 2013
 
American Journal of Audiology, March 2014, Vol. 23, 1-6. doi:10.1044/1059-0889(2013/13-0018)
History: Received March 25, 2012; Revised August 13, 2013; Accepted September 2, 2013
Web of Science® Times Cited: 5

Purpose The authors report on a 7-year-old male, designated FR, who has severe sensorineural hearing loss. Features include a round face, hypertelorism, epicanthal folds, and flat nasal root. Although there were early developmental concerns regarding FR, all but his speech delay resolved when he was placed in an educational program that accommodated his hearing loss. Genetic studies were performed to investigate genetic causes for his hearing loss.

Method History, physical examination, audiologic assessment, and imaging were performed according to usual practice. FMR1, GJB2, GJB6, and POU3F4 genes were sequenced. Chromosomal studies consisted of karyotyping and breakpoint analysis by fluorescence in situ hybridization (FISH).

Results Results from FMR1, GJB2, GJB6, and POU3F4 sequencing and echocardiography, electrocardiogram, and abdominal ultrasound were normal. A computed tomography (CT) scan revealed a large fundus of the internal auditory canals and absence of the bony partition between the fundus and the adjacent cochlear turns, with a widened modiolus bilaterally. FR's CT findings were consistent with those described in persons with X-linked deafness-2 (DFNX2) hereditary deafness. FR's karyotype was 46,inv(X)(q13q24),Y.ish inv(X)(XIST+)mat. FISH refined the breakpoints to inv(X)(q21.1q22.3). The Xq21.1 breakpoint was narrowed to a 25-kb region 450 kb centromeric to the DFNX2 gene, POU3F4. There are rare case reports of DFNX2 patients with chromosomal rearrangements positioned centromeric to POU3F4 and no mutations within the gene.

Conclusion Authors hypothesized that FR's hearing loss was caused by dysregulation of POU3F4 due to separation from regulatory elements affected by the inversion.

Acknowledgments
This research was supported by the Developmental Genome Anatomy Project (DGAP) by the National Institute of General Medical Sciences Grant P01 GM061354, awarded to the fifth author. We also thank Adriana Breen and Sarah Hori for assisting with preparation of this article.
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