Atypical autism in a boy with double duplication of 22q11.2: implications of increasing dosage

Breanne Dale,Beth Mcconnell,Bhooma Thiruvahindrapuram,Melissa T Carter,Jhoan Falcon,Sanne Jilderda,Ny Hoang,D James Stavropoulos,Irene E Drmic,Pooja Swaroop,Stephen W Scherer,Bonnie Mackinnon Modi,Susan Walker

doi:10.1038/s41525-017-0031-6

Breanne Dale, Beth Mcconnell + Show 11 more

Open Access

https://doi.org/10.1038/s41525-017-0031-6

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Abstract

Duplication of chromosome 22q11.2 (LCR A-D) has been reported at higher frequencies in clinical samples than the general population, but phenotypes vary widely. Triplication (4 copies) is rare, but studying the associated phenotype may provide insight into dosage-sensitivity of the genes in this chromosomal interval. We describe a proband with a triplication, specifically a “double duplication” (two copies per chromosome) of the 22q11.2 region, while his parents and two siblings each have a single duplication (3 copies). The proband had a heart malformation, dysmorphic features, and learning and socialization deficits, whereas the other family members did not. This family illustrates that while duplication of the 22q11.2 may not be sufficient to cause clinically significant neurodevelopmental or health-related phenotypes, triplication of the same region may result in a phenotype characterized by a mild neurodevelopmental disorder, facial dysmorphism, and possibly cardiac anomalies.

Highlights

The 22q11.2 chromosomal region is susceptible to rearrangements due to the presence of several low-copy repeat sequences.[1]
The 22q11.2 deletion syndrome has long been recognized as a heterogeneous condition characterized by congenital heart defect, cleft palate or velopharyngeal insufficiency, developmental delay, and a heightened predisposition to psychiatric disorders.[2]
Reports were identified by fluorescence in situ hybridization (FISH) analysis for suspicion of 22q11.2 deletion syndrome (22q11.2 DS), and were biased towards those with similar features.[5]

Summary

Introduction

The 22q11.2 chromosomal region is susceptible to rearrangements due to the presence of several low-copy repeat sequences.[1]. Copy number variant (CNV) analysis examining sequence read-depth of whole genome sequencing (WGS) data confirmed the duplications (data not shown). FISH testing of both parents confirmed a 2:1 configuration of the copy number gains at 22q11.2 and a 2:2 configuration in the proband (Supplementary Figure 1).

Results

Conclusion