22q13 Microduplication Syndrome in Siblings with Mild Clinical Phenotype: Broadening the Clinical and Behavioral Spectrum

Abstract

Distal duplication 22q (22q13.3qter) is a rare condition with only 24 cases described so far. Parental balanced reciprocal translocations and pericentric inversions involving chromosome 22 predispose to the conception of an unbalanced offspring and are more frequently reported than de novo events. The clinical phenotype of patients is highly variable and does not necessarily correlate with the extent of the duplicated segment. Short stature, microcephaly, hypertelorism, cleft lip or palate, low-set ears, and intellectual disability seem to be the most consistent features. Familial reoccurrence is extremely rarely reported. Here, we report 2 siblings with a 22q13.3qter duplication detected by array CGH; their mother is a carrier of a pericentric inversion in chromosome 22. Their relatively mild phenotype and identical chromosomal breakpoints as well as duplication size are unique. This is the first case described so far.

Keywords: 22q13; 22qter; Array CGH; Distal trisomy 22q; Pericentric inversion.

Fig. 1

A Patient 1 showing hypertelorism, divergent strabismus, broad eyebrows, high nasal bridge, bulbous tip of the nose, posteriorly low-inserted columella, small hands with tapering fingers, and an overall friendly nature. B Patient 2, brother of patient 1, with similar facial features. In addition, he has a deviated septum and more pronounced downslanting palpebral fissures.

Fig. 2

A FISH on metaphase spread of patient 1 using locus specific probe for 22q11.2 (TUPLE1; red) and 22q13.3 (N85A3; green). The latter covers the telomeric end of the SHANK3 gene, allowing the identification of the most distal 22q13.3 rearrangements. The abnormal chromosome 22 contains two 22q13.3 signals. B FISH on metaphase spread of the mother using locus specific probe for 22q11.2 (TUPLE1; red) and 22q13.3 (N85A3; green). The inv(22) shows the inverted chromosome 22 and relocation of the 22q13.3 region to the short arm. C Array CGH of the probands and the mother using Affymetrix 750K platform. The analysis shows the identical duplication (blue bars) of 3,327 kb involving the 22q13.31q13.33 region in patient 1 and 2, with the breakpoints falling between 47,870,362 and 51,197,766. The smaller duplication detected in the mother's sample (middle) contains no OMIM genes. Dashed lines represent copy number statuses.