Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother

Abstract

The pericentromeric region of chromosome 16p is rich in segmental duplications that predispose to rearrangements through non-allelic homologous recombination. Several recurrent copy number variations have been described recently in chromosome 16p. 16p11.2 rearrangements (29.5-30.1 Mb) are associated with autism, intellectual disability (ID) and other neurodevelopmental disorders. Another recognizable but less common microdeletion syndrome in 16p11.2p12.2 (21.4 to 28.5-30.1 Mb) has been described in six individuals with ID, whereas apparently reciprocal duplications, studied by standard cytogenetic and fluorescence in situ hybridization techniques, have been reported in three patients with autism spectrum disorders. Here, we report a multiplex family with three boys affected with autism, including two monozygotic twins carrying a de novo 16p11.2p12.2 duplication of 8.95 Mb (21.28-30.23 Mb) characterized by single-nucleotide polymorphism array, encompassing both the 16p11.2 and 16p11.2p12.2 regions. The twins exhibited autism, severe ID, and dysmorphic features, including a triangular face, deep-set eyes, large and prominent nasal bridge, and tall, slender build. The eldest brother presented with autism, mild ID, early-onset obesity and normal craniofacial features, and carried a smaller, overlapping 16p11.2 microdeletion of 847 kb (28.40-29.25 Mb), inherited from his apparently healthy father. Recurrent deletions in this region encompassing the SH2B1 gene were recently reported in early-onset obesity and in individuals with neurodevelopmental disorders associated with phenotypic variability. We discuss the clinical and genetic implications of two different 16p chromosomal rearrangements in this family, and suggest that the 16p11.2 deletion in the father predisposed to the formation of the duplication in his twin children.

Figure 1

Photos of patients 1–3. (a) Patient 1, showing some unusual facial features (deep-set eyes, thick supra-orbital ridge with thick eyebrows, wide and prominent nasal bridge, receding chin and everted lower lip). (b, c) Patient 2 (left) and 3 (right); note similar dysmorphic features with hypertelorism, upslanting palpebral fissures, broad nasal bridge and tip, everted lower lip and retrognathia with marked chin. (d) Sternum deformity in patient 2 (also present in his twin brother).

Figure 2

Microarray and qPCR results. (a) SNP array profiles of chromosome 16 showing a 16p11.2 deletion in patient 1, inherited from his father (both highlighted in red), a de novo 16p11.2p12.1 duplication in patient 2 (highlighted in blue), and a normal profile in the mother. (b) qPCR probes confirmed the 16p11.2p12.2 duplication in the twins (patients 2 and 3) and the 16p11.2 deletion in patient 1 and the father compared with three controls. Data represent mean±SEM. The color reproduction of this figure is available at European Journal of Human Genetics journal online.

Figure 3

Map of the short arm of chromosome 16 with a summary of abnormalities identified in the 16p11.2-p12.2 region. Schematic representation of chromosome 16p showing the 16p11.2-p12.2 duplication in patients 2 and 3 (thick blue line) and other overlapping rearrangements reported previously: four duplications (thin blue lines), six deletions (red lines) and one complex rearrangement involving a duplication and a triplication (purple line). The location of five recurrent microdeletion/microduplication syndromes is represented by blue rectangles on the ideogram. A detailed map of ∼9 Mb (21177300-30296811, hg 18), comprising the duplication in patients 2 and 3 (thick blue line) and the deletion in patient 1 and the father (thick red line) is shown. Additional horizontal thin red lines indicate deletions described previously in individuals with obesity, developmental delay (DD), learning disability (LD), congenital anomalies of the kidney and urinary tract (CAKUT), or Hirschsprung disease (HSCR). The patient marked with an asterisk was too young to evaluate the manifestations reliably. qPCR probes are shown as vertical bars; black bars represent a normal copy number, blue bars indicate a duplication (in patients 2 and 3) and red bars indicate a deletion (in patient 1 and the father). Horizontal green lines indicate the location of structural variations identified in non-bacterial artificial chromosomes studies according to the Database of Genomic Variants (DGV). The inset shows a simplified interpretation of the segmental duplications located in the 16p11.2-p12.2 region (UCSC genome browser). See Supplementary Note for a detailed description of these segmental duplications and their possible role in the observed rearrangements in the family described here. The color reproduction of this figure is available at European Journal of Human Genetics journal online.

Figure 4

Proposed mechanism for the formation of the 16p11.2-p12.2 duplication in the twins. (a) Chromosome 16p region comprising the duplication in the twins (blue line) and the 16p11.2 deletion in the father (red line). Blocks of segmental duplications in the same orientation with a high degree of identity overlapping the breakpoint regions are represented by green arrows (see Supplementary note for details). Letters A–E indicate the chromosomal regions represented in the panels below. (b) One of the paternal chromosomes (orange) carries a deletion of the segment identified as C. During meiosis, the normal chromosome (blue) forms a deletion loop; the genome architecture of the region facilitates misalignment of directly oriented segmental duplications, followed by NAHR within the loop. (c) Interchromatid mispairing of direct repeats results in duplication (the recombinant product transmitted to the twins) and deletion. The color reproduction of this figure is available at European Journal of Human Genetics journal online.