Characterization of a 8q21.11 microdeletion syndrome associated with intellectual disability and a recognizable phenotype

Abstract

We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid's bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.

Figure 1

Facial Views of Individuals Included in the Present Study (A) Individual 1 at age 4 (left) and 7 years (right). (B) Individual 3 at age 1 month (left) and 6 years (middle and right). (C) Individual 2 at age 6 months. (D) Individual 4 at age 17 years (left and right). (E) Individual 5 at age 12 years (left and right). (F) Individual 6 at age 20 months (left) and 9 years (right). (G) Individual 7 at age 15 years (left and right) and (H) individual 8 at age 3 years.

Figure 2

Graphical Representation of the Deletions in All Individuals and Genes within the Minimal Region of Overlap The minimal region of overlap shown includes hg 19, chromosome 8: 77226464-77766239.

Figure 3

FISH Confirmation of the Heterozygous Deletion of 8q21 in Individuals Individuals 1 (A), 2 (B), and 3 (C) are shown with BAC probe RP11-48D4 mapping to 8q21.11 (red).