X-Linked Deafness-2 (DFNX2) Phenotype Associated With a Paracentric Inversion Upstream of POU3F4

Abstract

Purpose The authors report a seven-year-old male, designated FR, with severe sensorineural hearing loss. Features include round face, hypertelorism, epicanthal folds, and flat nasal root. Although there were early developmental concerns, all but his speech delay resolved when he was placed in an educational program that accommodated his hearing loss. To investigate genetic causes for his hearing loss, genetic studies were performed. Methods 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, ECG, and abdominal ultrasound were normal. CT 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. CT findings are consistent with those described in persons with DFNX2 hereditary deafness. His 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. Conclusions We hypothesize that FR's hearing loss is caused by dysregulation of POU3F4 due to separation from regulatory elements affected by the inversion.

Human inversions and their functional consequences

“…In addition, despite the possible effects on fertility owing to the unbalanced chromosomes resulting from a crossover within the inverted region in heterozygotes, for some of these inversions no increased risk for miscarriage or problems in chromosome segregation during meiosis have been observed [ 55 , 56 ]. Not all inversions are harmless, however, and several diseases have been found to be occasionally caused by inversions, mostly by direct disruption of one gene [ 57 , 58 ] or by altering its gene expression [ 59 , 60 ]. These inversions appear de novo in patients or are inherited mutations restricted to a given family, and thus they do not represent polymorphic variants segregating in human populations.…”

Position effect, cryptic complexity, and direct gene disruption as disease mechanisms in de novo apparently balanced translocation cases

“…Structural variants upstream the coding POU3F4 region, including microdeletions, inversions, and duplications, have also been reported in patients with similar hearing loss phenotypes, thus indicating the presence of cis -regulatory elements (e.g. enhancers) within those regions (even up to 900kb upstream), which if disturbed result in altered POU3F4 expression through LRPE [ 25 – 27 ]. The majority of POU3F4 disruption cases have been reported in affected males.…”

Genetic Causes of Inner Ear Anomalies: a Review from the Turkish Study Group for Inner Ear Anomalies

“…The X-linked POU3F4 gene is the first nuclear gene implicated in nonsyndromic deafness. The type of HL may be SNHL or mixed and associated with IP-III (incomplete partition type 3), cochlear hypoplasia, and/or stapes fixation (DFN3) (36,37,38,39). In addition to mutations located within the gene, copy number variants not involving the coding part of the gene have been reported; de Kok et al (40) identified a hot spot for microdeletions in patients with X-linked deafness 900 kb proximal to the DFN3 gene.…”