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.2011 Jan;48(1):48-54.
doi: 10.1136/jmg.2010.079426. Epub 2010 Oct 23.

Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability

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Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability

Alistair T Pagnamenta et al. J Med Genet.2011 Jan.

Abstract

Background: Autism spectrum disorder (ASD) is characterised by impairments in social communication and by a pattern of repetitive behaviours, with learning disability (LD) typically seen in up to 70% of cases. A recent study using the PPL statistical framework identified a novel region of genetic linkage on chromosome 16q21 that is limited to ASD families with LD.

Methods: In this study, two families with autism and/or LD are described which harbour rare >1.6 Mb microdeletions located within this linkage region. The deletion breakpoints are mapped at base-pair resolution and segregation analysis is performed using a combination of 1M single nucleotide polymorphism (SNP) technology, array comparative genomic hybridisation (CGH), long-range PCR, and Sanger sequencing. The frequency of similar genomic variants in control subjects is determined through analysis of published SNP array data. Expression of CDH8, the only gene disrupted by these microdeletions, is assessed using reverse transcriptase PCR and in situ hybridisation analysis of 9 week human embryos.

Results: The deletion of chr16: 60 025 584-61 667 839 was transmitted to three of three boys with autism and LD and none of four unaffected siblings, from their unaffected mother. In a second family, an overlapping deletion of chr16: 58 724 527-60 547 472 was transmitted to an individual with severe LD from his father with moderate LD. No copy number variations (CNVs) disrupting CDH8 were observed in 5023 controls. Expression analysis indicates that the two CDH8 isoforms are present in the developing human cortex.

Conclusion: Rare familial 16q21 microdeletions and expression analysis implicate CDH8 in susceptibility to autism and LD.

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Conflict of interest statement

Competing interests: None.

Figures

Figure 1
Figure 1
Schematic from the UCSC genome browser. Figure shows the position of the two inherited deletions overlappingCDH8, in relation to the low IQ autism spectrum disorder (ASD) linkage peak from our recent analysis. The y axis indicates the PPL score. RefSeq gene coordinates are also plotted beneath the chromosome band track. The region shown corresponds to 54–65 Mb on 16q12.2-21 (NCBI build 36 coordinates).
Figure 2
Figure 2
Deletions found in families 3099 and 09. (A) Pedigrees show the segregation pattern for these two deletions involvingCDH8. Autism and learning disability indicated in black shading, learning disability alone indicated in grey; del, 16q21 deletion; wt, wild-type. Although individual 09_004 demonstrated typical IQ scores, he was reported to have been in treatment for language delay and learning disabilities between the ages of 7 and 11 years. (B) Electropherogram showing DNA sequence spanning the chr16:60 025 584–61 667 839 (NCBI build 36) deletion in family 3099. (C) Electropherogram showing DNA sequence spanning the chr16:58 724 527–60 547 472 deletion in family 09. The position of a 7 bp tandem duplication is indicated.
Figure 3
Figure 3
Expression analysis ofCDH8. (A) Reverse transcriptase PCR (RT-PCR) analysis detected a 1760 bp amplicon corresponding to the shortCDH8 isoform. (B) RT-PCR analysis detected a 2514 bp product (boxed), corresponding to the longerCDH8 isoform. (C) In situ hybridisation performed on sagittal sections through the head of a 9-week-old human embryo, for the shortCDH8 isoform. (D) In situ hybridization for the longer isoform. Arrows indicate cortical expression.
See this image and copyright information in PMC

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