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A family with autism and rare copy number variants disrupting the Duchenne/Becker muscular dystrophy gene DMD and TRPM3.

Pagnamenta AT, Holt R, Yusuf M, Pinto D, Wing K, Betancur C, Scherer SW, Volpi EV, Monaco AP - J Neurodev Disord (2011)

Bottom Line: The DMD reading frame rule predicts a Becker phenotype, characterised by later onset and milder symptoms.When last evaluated, neither child had developed signs of muscular dystrophy.Finally, communicating unexpected findings such as these back to families raises a number of ethical questions, which are discussed.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.

ABSTRACT
Autism spectrum disorder is a genetically complex and clinically heterogeneous neurodevelopmental disorder. A recent study by the Autism Genome Project (AGP) used 1M single-nucleotide polymorphism arrays to show that rare genic copy number variants (CNVs), possibly acting in tandem, play a significant role in the genetic aetiology of this condition. In this study, we describe the phenotypic and genomic characterisation of a multiplex autism family from the AGP study that was found to harbour a duplication of exons 31-44 of the Duchenne/Becker muscular dystrophy gene DMD and also a rare deletion involving exons 1-9 of TRPM3. Further characterisation of these extremely rare CNVs was carried out using quantitative PCR, fluorescent in situ hybridisation, long-range PCR amplification and sequencing of junction fragments. The maternal chrX:32,097,213-32,321,945 tandem duplication and paternal chr9:72,480,413-73,064,196 deletion (NCBI build 36 coordinates) were transmitted to both affected boys, potentially signifying a multi-hit mechanism. The DMD reading frame rule predicts a Becker phenotype, characterised by later onset and milder symptoms. When last evaluated, neither child had developed signs of muscular dystrophy. These data are consistent with a degree of comorbidity between autism and muscular dystrophy and suggest that genomic background as well as the position of the mutation within the DMD gene may impact on the neurological correlates of Duchenne/Becker muscular dystrophy. Finally, communicating unexpected findings such as these back to families raises a number of ethical questions, which are discussed.

No MeSH data available.


Related in: MedlinePlus

Segregation of two rare CNVs in family 3019. a qPCR results for fine mapping distal and proximal ends of the DMD duplication. Results are normalised to a qPCR assay from outside the duplicated region and then compared to the father for whom the 1M SNP array indicated did not have the duplication. ASS alternative start site. b Agarose gel showing long-range PCR products. Presence of the TRPM3 deletion is indicated by an ∼8-kb fragment. c Pedigree summarising CNV status. Shaded symbols correspond to autism. Blue and red fonts indicate most likely maternal TRPM3 haplotype flow, as determined using Merlin analysis of 10K SNP data. Birth order has been switched to ensure family anonymity
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Fig1: Segregation of two rare CNVs in family 3019. a qPCR results for fine mapping distal and proximal ends of the DMD duplication. Results are normalised to a qPCR assay from outside the duplicated region and then compared to the father for whom the 1M SNP array indicated did not have the duplication. ASS alternative start site. b Agarose gel showing long-range PCR products. Presence of the TRPM3 deletion is indicated by an ∼8-kb fragment. c Pedigree summarising CNV status. Shaded symbols correspond to autism. Blue and red fonts indicate most likely maternal TRPM3 haplotype flow, as determined using Merlin analysis of 10K SNP data. Birth order has been switched to ensure family anonymity

Mentions: In this third family, a maternally inherited duplication of Xp21.1 was detected in subject 3019.3 during a large genome-wide scan for CNVs (Pinto et al. 2010). After manual inspection of the log R ratios and B allele frequencies in BeadStudio, the maximal and minimal duplicated region was determined to be from rs16990134 to rs5972556 and from rs1795588 to rs1555256, respectively (ESM Fig. 1a). At the proximal end, this resolution was not sufficient to determine which combination of exons had been duplicated. Therefore, qPCR was used to validate and resolve the mutation further. These data showed that the duplication involved exons 31–44 (Fig. 1a) and so is predicted to leave the reading frame intact. These qPCR results also indicated that the affected brother (3019.5) had inherited the same mutation from the mother, whilst the unaffected sister did not carry this variant (Fig. 1a).Fig. 1


A family with autism and rare copy number variants disrupting the Duchenne/Becker muscular dystrophy gene DMD and TRPM3.

Pagnamenta AT, Holt R, Yusuf M, Pinto D, Wing K, Betancur C, Scherer SW, Volpi EV, Monaco AP - J Neurodev Disord (2011)

Segregation of two rare CNVs in family 3019. a qPCR results for fine mapping distal and proximal ends of the DMD duplication. Results are normalised to a qPCR assay from outside the duplicated region and then compared to the father for whom the 1M SNP array indicated did not have the duplication. ASS alternative start site. b Agarose gel showing long-range PCR products. Presence of the TRPM3 deletion is indicated by an ∼8-kb fragment. c Pedigree summarising CNV status. Shaded symbols correspond to autism. Blue and red fonts indicate most likely maternal TRPM3 haplotype flow, as determined using Merlin analysis of 10K SNP data. Birth order has been switched to ensure family anonymity
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105230&req=5

Fig1: Segregation of two rare CNVs in family 3019. a qPCR results for fine mapping distal and proximal ends of the DMD duplication. Results are normalised to a qPCR assay from outside the duplicated region and then compared to the father for whom the 1M SNP array indicated did not have the duplication. ASS alternative start site. b Agarose gel showing long-range PCR products. Presence of the TRPM3 deletion is indicated by an ∼8-kb fragment. c Pedigree summarising CNV status. Shaded symbols correspond to autism. Blue and red fonts indicate most likely maternal TRPM3 haplotype flow, as determined using Merlin analysis of 10K SNP data. Birth order has been switched to ensure family anonymity
Mentions: In this third family, a maternally inherited duplication of Xp21.1 was detected in subject 3019.3 during a large genome-wide scan for CNVs (Pinto et al. 2010). After manual inspection of the log R ratios and B allele frequencies in BeadStudio, the maximal and minimal duplicated region was determined to be from rs16990134 to rs5972556 and from rs1795588 to rs1555256, respectively (ESM Fig. 1a). At the proximal end, this resolution was not sufficient to determine which combination of exons had been duplicated. Therefore, qPCR was used to validate and resolve the mutation further. These data showed that the duplication involved exons 31–44 (Fig. 1a) and so is predicted to leave the reading frame intact. These qPCR results also indicated that the affected brother (3019.5) had inherited the same mutation from the mother, whilst the unaffected sister did not carry this variant (Fig. 1a).Fig. 1

Bottom Line: The DMD reading frame rule predicts a Becker phenotype, characterised by later onset and milder symptoms.When last evaluated, neither child had developed signs of muscular dystrophy.Finally, communicating unexpected findings such as these back to families raises a number of ethical questions, which are discussed.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.

ABSTRACT
Autism spectrum disorder is a genetically complex and clinically heterogeneous neurodevelopmental disorder. A recent study by the Autism Genome Project (AGP) used 1M single-nucleotide polymorphism arrays to show that rare genic copy number variants (CNVs), possibly acting in tandem, play a significant role in the genetic aetiology of this condition. In this study, we describe the phenotypic and genomic characterisation of a multiplex autism family from the AGP study that was found to harbour a duplication of exons 31-44 of the Duchenne/Becker muscular dystrophy gene DMD and also a rare deletion involving exons 1-9 of TRPM3. Further characterisation of these extremely rare CNVs was carried out using quantitative PCR, fluorescent in situ hybridisation, long-range PCR amplification and sequencing of junction fragments. The maternal chrX:32,097,213-32,321,945 tandem duplication and paternal chr9:72,480,413-73,064,196 deletion (NCBI build 36 coordinates) were transmitted to both affected boys, potentially signifying a multi-hit mechanism. The DMD reading frame rule predicts a Becker phenotype, characterised by later onset and milder symptoms. When last evaluated, neither child had developed signs of muscular dystrophy. These data are consistent with a degree of comorbidity between autism and muscular dystrophy and suggest that genomic background as well as the position of the mutation within the DMD gene may impact on the neurological correlates of Duchenne/Becker muscular dystrophy. Finally, communicating unexpected findings such as these back to families raises a number of ethical questions, which are discussed.

No MeSH data available.


Related in: MedlinePlus