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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

Further molecular characterisation of both rare CNVs. a Fibre FISH images from normal X chromosome from mother (upper) and duplicated X chromosome from proband (lower). Schematic shows DMD duplicons alongside position of primers used for long-range PCR. b Interphase and metaphase FISH images from proband for the TRPM3 locus. The deleted chromosome 9 is missing the signal from the RP11-89K20 probe (green). c Electropherograms with breakpoint-spanning sequences across the DMD duplication (upper) and TRPM3 deletion (lower)
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Fig2: Further molecular characterisation of both rare CNVs. a Fibre FISH images from normal X chromosome from mother (upper) and duplicated X chromosome from proband (lower). Schematic shows DMD duplicons alongside position of primers used for long-range PCR. b Interphase and metaphase FISH images from proband for the TRPM3 locus. The deleted chromosome 9 is missing the signal from the RP11-89K20 probe (green). c Electropherograms with breakpoint-spanning sequences across the DMD duplication (upper) and TRPM3 deletion (lower)

Mentions: Although the SNP array and qPCR confirmed that exons 31–44 of DMD were duplicated, they could not distinguish whether the extra segment of DNA was situated in tandem with the normal copy or at a different genomic locus. Fibre FISH using BAC and fosmid probes confirmed that the duplication was in a direct tandem repeat orientation (Fig. 2a) and therefore that the functional copy of DMD was disrupted.Fig. 2


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)

Further molecular characterisation of both rare CNVs. a Fibre FISH images from normal X chromosome from mother (upper) and duplicated X chromosome from proband (lower). Schematic shows DMD duplicons alongside position of primers used for long-range PCR. b Interphase and metaphase FISH images from proband for the TRPM3 locus. The deleted chromosome 9 is missing the signal from the RP11-89K20 probe (green). c Electropherograms with breakpoint-spanning sequences across the DMD duplication (upper) and TRPM3 deletion (lower)
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105230&req=5

Fig2: Further molecular characterisation of both rare CNVs. a Fibre FISH images from normal X chromosome from mother (upper) and duplicated X chromosome from proband (lower). Schematic shows DMD duplicons alongside position of primers used for long-range PCR. b Interphase and metaphase FISH images from proband for the TRPM3 locus. The deleted chromosome 9 is missing the signal from the RP11-89K20 probe (green). c Electropherograms with breakpoint-spanning sequences across the DMD duplication (upper) and TRPM3 deletion (lower)
Mentions: Although the SNP array and qPCR confirmed that exons 31–44 of DMD were duplicated, they could not distinguish whether the extra segment of DNA was situated in tandem with the normal copy or at a different genomic locus. Fibre FISH using BAC and fosmid probes confirmed that the duplication was in a direct tandem repeat orientation (Fig. 2a) and therefore that the functional copy of DMD was disrupted.Fig. 2

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