Duplication 2p25 in a child with clinical features of CHARGE syndrome

Abstract

CHARGE syndrome is a dominant disorder characterized by ocular colobomata, heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear abnormalities including deafness and vestibular disorders. The majority of individuals with CHARGE have pathogenic variants in the gene encoding CHD7, a chromatin remodeling protein. Here, we present a 15-year-old girl with clinical features of CHARGE syndrome and a de novo 6.5 Mb gain of genomic material at 2p25.3-p25.2. The duplicated region contained 24 genes, including the early and broadly expressed transcription factor gene SOX11. Analysis of 28 other patients with CHARGE showed no SOX11 copy number changes or pathogenic sequence variants. To our knowledge, this child's chromosomal abnormality is unique and represents the first co-occurrence of duplication 2p25 and clinical features of CHARGE syndrome. We compare our patient's phenotype to ten previously published patients with isolated terminal duplication 2p, and elaborate on the clinical diagnosis of CHARGE in the context of atypical genetic findings.

Keywords: CHARGE syndrome; duplication 2p25; gene duplication; trisomy 2p.

Figure 1

Clinical features of the proband. Photographs taken at 11 years show a broad, sloping forehead with a slender, prominent nose and flattened nasal tip (A–C). Over-folded helices (D–E), shortened proximal phalanges of the thumbs (F), and elongated fingers and toes (F–G) are noted.

Figure 2

Chromosomal microarray analysis revealed a gain of genomic material on chromosome 2p25.3-p25.2, confirmed by FISH, and shared with three other cases. CMA performed on whole blood revealed a de novo, distal duplication and proximal triplication of 2p25.3-p25.2 (A, highlighted in red). Interphase FISH confirmed the CMA findings, revealing a distal duplication (B, green probe RP11-168K7) and proximal triplication (C, green probe RP11-36C8). Red label in (B) and (C) corresponds to a 2qter probe, indicating normal dosage of 2q in each case. Visualization of pachytene chromosomes using prophase FISH (D) confirmed probe arrangement along 2p, confirmed the integrity of the 2p subtelomeric region (2pter red probe), and excluded translocation events. The 24 genes contained within the interval duplicated within our patient are shown (E). In our patient’s diploid genome, the 11 distal genes were present in triplicate while the 13 proximal genes were in quadruplicate. Of interest, our patient had four copies of SOX11, an SRY-related HMG box-containing SoxC group transcription factor.