NR2F1 deletion in a patient with a de novo paracentric inversion, inv(5)(q15q33.2), and syndromic deafness

Abstract

In an effort to discover genes important for human development, we have ascertained patients with congenital anomalies and cytogenetically balanced chromosomal rearrangements. Herein, we report a 4-year-old girl with profound deafness, a history of feeding difficulties, dysmorphism, strabismus, developmental delay, and an apparently balanced de novo paracentric chromosome 5 inversion, inv(5)(q15q33.2). Molecular cytogenetic analysis of the inversion revealed the presence of microdeletions of approximately 400-500 kb at or near both breakpoints. The 5q15 microdeletion completely removes the nuclear receptor NR2F1 (COUP-TFI) from the inverted chromosome 5. We propose haploinsufficiency of NR2F1 to be the cause of the patient's deafness and many of the other associated anomalies based on striking similarity with the Nr2f1 null mouse. Additionally, this study further highlights the need for high resolution analysis of clinical samples with chromosomal rearrangements as associated deletions may be primarily responsible for the clinical features of these patients.

Figure 1

Front and side views of DGAP169 at 11 weeks of age. Note the low-set, small, malformed ears, unusual pattern of hair growth, upslanting palpebral fissures, broad nasal tip, anteverted nares, and micrognathia. The face is also asymmetric with the eyes positioned at slightly different levels. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 2

CT images of DGAP169 temporal bone. a) The malformed stapes is indicated by the arrow. b) The malformed malleus is indicated by the arrow. c) The asterisk marks the underdeveloped middle and apical turns of the cochlea, while the arrow marks the abnormal path of the facial nerve through the mastoid bone. d) The abnormal course of the facial nerve through the middle ear is indicated by the arrow.

Figure 3

FISH results on DGAP169 metaphase chromosomes using chromosome 5 BAC probes. a) BAC RP11-108e6 (red) maps to 5q15 and spans the 5q15 inversion breakpoint. b) BAC CTD-3236h3 (red) maps to 5q15 and is deleted from the inv(5). BAC RP11-790o1 (green) at 5q33.2 marks chromosome 5. C) BAC RP11-635k22 (green) maps to 5q33.2 and is deleted from the inv(5). BAC RP11-521h6 (red) at 5q15 marks chromosome 5. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 4

Maps of the inv(5)(q15q33.2) breakpoint regions from the UCSC genome browser. a) Map of 5q15 showing the breakpoint region and the deleted region centromeric to the breakpoint. b) Map of 5q33.2 showing the region deleted by the breakpoint. The red portion of the line at the bottom of each section shows the minimal deleted regions. The grey portions of the line show the maximal deleted regions. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]