Transmitted duplication of 8p23.1-8p23.2 associated with speech delay, autism and learning difficulties

Abstract

Duplications of distal 8p with and without significant clinical phenotypes have been reported and are often associated with an unusual degree of structural complexity. Here, we present a duplication of 8p23.1-8p23.2 ascertained in a child with speech delay and a diagnosis of ICD-10 autism. The same duplication was found in his mother who had epilepsy and learning problems. A combination of cytogenetic, FISH, microsatellite, MLPA and oaCGH analysis was used to show that the duplication extended over a minimum of 6.8 Mb between 3 539 893 and 10 323 426 bp. This interval contains 32 novel and 41 known genes, of which only microcephalin (MCPH1) is a plausible candidate gene for autism at present. The distal breakpoint of the duplicated region interrupts the CSMD1 gene in 8p23.2 and the medial breakpoint lies between the MSRA and RP1L1 genes in 8p23.1.An interchromosomal insertion between a normal and polymorphically inverted chromosome 8 is proposed to explain the origin of this duplication. Further mapped imbalances of distal 8p are needed to determine whether the autistic component of the phenotype in this family results from the cumulative imbalance of many genes or dosage imbalance of an individual susceptibility gene.

Figure 1

(A and B) Partial karyotypes of (a) the proband and (b) his mother. Note the increased interval between bands p22 and p23.2 and the additional G-dark in the proximal part of the increased interval (arrowed on the right hand duplicated chromosome in each case). (B) Idiogram of the proposed insertional duplication of distal 8p23.1–8p23.2 from a normal chromosome 8 into a polymorphically inverted chromosome 8 adjacent to REPP/D in proximal 8p23.1. On the left hand normal chromosome, distal 8p23.1 is in white, REPD is in blue, REPP is in purple, the interval between them in yellow and proximal 8p23.1 in white again. The double-headed vertical red arrow indicates the extent of the duplication on the normal chromosome and the vertical black upward arrow next to BACs RP11-211C9 and RP11-589N15 indicates the ‘genome browser' orientation of the REPP to REPD interval. In the central chromosome, REPP and REPD are shown in both colours as the result of the common polymorphic inversion and the horizontal single-headed red arrow indicates the proposed point of insertion adjacent to the composite REPD/P repeat. The duplicated chromosome is on the right with the vertical double-headed red arrows showing the position and extent of the duplication. Duplicated BACs are shown in blue and the BAC, which gave three signals (RP11-122N11) is in turquoise. Note the orientation of the duplicated BACs is the same as that on the left hand normal chromosome. By contrast, the reverse order of BACs RP11-589N15 and RP11-211C9 is indicated by the downward vertical black arrow.

Figure 2

(a–d) Representative dual colour FISH in metaphases from the proband and mother; (a) direct duplication of both RP11-16H11 (red) from 8p23.2 and RP11-211C9 from 8p23.1 (green) in the proband; (b) the duplication of RP11-211C9 (green) alternating between three distinct RP11-122N11 signals (red) in a higher resolution cell in the mother; (c) direct duplication of both RP5-991O23 (red) from 8p23.2 and CTD-2629I16 from 8p23.1 (green) in the mother; (d) the single-copy RP11-589N15 signals (green) located very distally within the block of signals from RP11-122N11 in the mother. (e) Agilent 44K oligonucleotide array result from the proband analysed with Analytics v3.3 software. The black arrows point to the normal and duplicated clones that flank the duplication with the base pairs given for the p-telomeric edge of each oligonucleotide probe (see also Table 1).