A de novo 6p interstitial deletion and a complex translocation involving chromosomes 2, 6, and 14 in a mildly developmentally delayed patient

Abstract

Constitutional complex chromosome rearrangements (CCRs) involve two or more breakpoints with exchange of segments among at least two chromosomes [Pai et al., 1980]. A combined technical approach (G banding, aCGH, and FISH) documented a de novo CCR in our patient. The patient was born at term with normal birth weight after an uneventful pregnancy. He has healthy, nonconsanguineous parents (the mother was 35, the father 38 years old), and healthy siblings. As a baby he was quiet and slept excessively. He walked at 15 months. At 3 years he was referred for a chromosome analysis because of global delayed development and minor anomalies. At 5 years he lagged around 1 year behind his peers. Language development was most delayed, especially pronunciation. At 5 years he could put two to three words together, but it was difficult to understand him. No anatomic malformations were identified that could explain his language difficulties. Motor development was only slightly delayed and no hypotonia was noted. He also has deep set eyes, a prominent philtrum, and a slightly prominent forehead (Fig. 1). In addition, his ears are slightly low set and posteriorly angulated, with normal shape. A physical eye examination at the age of 6.5 years old showed: (1) 3 mm chorioretinal coloboma inferonasally in the left eye; (2) hypermetropia of 2.5 diopters bilaterally and minor exophoria; (3) hypertelorism with an interpupillary distance (IPD) of 62 mm (>97th centile), inner canthal distance (ICD) of 35 mm (97th centile), and outer canthal distance (OCD) of 84 mm (75th centile) [Dollfus and Verloes, 2004]. He has atopic dermatitis and asthma. Gbanding at standard resolution, followedbyFISH with Whole Painting Libraries from chromosomes 2, 6, and 14, and with 2qtel and 6qtel probes (Vysis, Abbott Molecular Inc., Downers Grove, IL), defined the karyotype of the propositus as: 46,XY, t(2,6,14) der (2)(2pter ! 2q33.3::6p24.1 ! 6pter), der(6) (2qter>2q33.3::14q24.3! 14q11.2::6p24.1! 6qter), der(14)(14pter ! 14q11.2::14q24.3 ! 14qter).ish der(2)(wcp2þ,wcp6þ,tel6pþ).ish der(6)(wcp6þ, wcp14þ ,wcp2þ , tel2qþ ) . ish der (14)(wcp14þ) (Fig. 2). Array-CGH (44k B oligo array, Agilent Technologies, Santa Clara, CA; data analysis by BlueFuse, BlueGnome, Cambridge, UK) detected a deletion on chr6:7933252–10510600 bp, a duplication on chr7:142863310–143726151 bp, and a deletion on chr14:18590766–19851375 bp (supporting information Table I may be found in the online version of this article). Thepositionsof the aberrations refer toNCBI Build 35. The duplicated region on chromosome 7 was not studied further because it corresponds to a known Copy Number Variant (CNV, http://projects.tcag.variation). The chromosome 14 deletion also corresponds to a known CNV and it is enriched with intraand inter-chromosome segmental duplications. This region, however, was analyzed by FISH