Microdeletion and Microduplication of 15q11.2-q13 share a neurodevelopmental phenotype
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Introduction: Individuals with the 15q11.2 microdeletion present with a constellation of neuropsychiatric and/or neurodevelopmental phenotypes including autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), developmental delay, obsessive compulsive disorder, and frequently seizure disorder. Similarly, individuals with 15q11q13 microduplication present with autism spectrum disorder (ASD), intellectual disability, hypotonia, developmental delay and seizure disorder (SD). Structurally, the microduplication may be interstitial or may be detected as a small supernumerary marker chromosome. The microduplication has a predilection for maternal inheritance in which case symptoms are more severe. In both microdeletion and microduplication cases, the chromosomal abnormality may de novo, or inherited. The microdeletion anomaly may encompass a smaller deletion within the larger 15q11.2q13 Praeder–Willi/Angelman (PWS/AS) region. It may not include the imprinted genes in the PWS/AS critical region.
Methods:
We report four cases of these copy number variants in four patients including three male probands, one mother who was found to carry the microduplication but did not exhibit the phenotype, and a mother with the phenotype but who was not available for microarray testing. Cases were ascertained through a genera pediatric clinic with a large case load of patients with neurodevelopmental disorders. Patients presenting with a neurodevelopmental phenotype characterized by varying degrees of impaired executive function, emotional regulation, cognition, learning and social adaptation underwent microarray testing. Parents of patients found to have copy number variants, were offered targeted microarray testing to determine inheritance.
Results:
Case 1 - CD – Presented with developmental delay, emotional dysregulation, attention deficit hyperactivity disorder, features of autism spectrum disorder. Dad had no history of the neuropsychiatric and/or neurodevelopmental phenotype and microarray was negative for the chromosomal anomaly. Mom was not available for testing, but was suspected to carry the chromosomal abnormality as has characteristic phenotype associated with the 15q11.2 microdeletion.
Case 2 – BW - Presented with developmental delay, deficits in social function, and was subsequently diagnosed with autism spectrum disorder. Mother of case 2 (Case 3 – AW- ) carries the chromosome 15q11.2 microduplication but did not have the phenotype.
Case 4 - FF – Presented with developmental delay, deficits in social function, sensory sensitivity, and seizures. A microarray showed a copy number variant characterized by a triplication involving chromosomal region 15q11.1q13.2 and duplication involving chromosomal region 15q13.2q13.3. Both mom and dad tested negative for chromosomal abnormality.
Conclusion:
The patients reported had various sizes of microdeletion and microduplication and yet shared a neurodevelopmental phenotype characterized by varying degrees of impaired executive function, emotional regulation, cognition, learning and social adaptation. This shared phenotype has been observed in certain neurodevelopmental disorders including ASD, ADHD, SD, fragile X syndrome, and fetal alcohol spectrum disorder. This suggests that the genes affected in these chromosomal abnormalities are involved in a common etiopathogenic endophenotype. Four OMIM morbid genes found in the 15d11.2 copy number variation region have been functionally associated with neurodevelopmental disorders mentioned above. Further characterization of the functional relationships could lead to the development of a common treatment strategy for several neurodevelopmental disorders.
Introduction: Individuals with the 15q11.2 microdeletion present with a constellation of neuropsychiatric and/or neurodevelopmental phenotypes including autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), developmental delay, obsessive compulsive disorder, and frequently seizure disorder. Similarly, individuals with 15q11q13 microduplication present with autism spectrum disorder (ASD), intellectual disability, hypotonia, developmental delay and seizure disorder (SD). Structurally, the microduplication may be interstitial or may be detected as a small supernumerary marker chromosome. The microduplication has a predilection for maternal inheritance in which case symptoms are more severe. In both microdeletion and microduplication cases, the chromosomal abnormality may de novo, or inherited. The microdeletion anomaly may encompass a smaller deletion within the larger 15q11.2q13 Praeder–Willi/Angelman (PWS/AS) region. It may not include the imprinted genes in the PWS/AS critical region.
Methods:
We report four cases of these copy number variants in four patients including three male probands, one mother who was found to carry the microduplication but did not exhibit the phenotype, and a mother with the phenotype but who was not available for microarray testing. Cases were ascertained through a genera pediatric clinic with a large case load of patients with neurodevelopmental disorders. Patients presenting with a neurodevelopmental phenotype characterized by varying degrees of impaired executive function, emotional regulation, cognition, learning and social adaptation underwent microarray testing. Parents of patients found to have copy number variants, were offered targeted microarray testing to determine inheritance.
Results:
Case 1 - CD – Presented with developmental delay, emotional dysregulation, attention deficit hyperactivity disorder, features of autism spectrum disorder. Dad had no history of the neuropsychiatric and/or neurodevelopmental phenotype and microarray was negative for the chromosomal anomaly. Mom was not available for testing, but was suspected to carry the chromosomal abnormality as has characteristic phenotype associated with the 15q11.2 microdeletion.
Case 2 – BW - Presented with developmental delay, deficits in social function, and was subsequently diagnosed with autism spectrum disorder. Mother of case 2 (Case 3 – AW- ) carries the chromosome 15q11.2 microduplication but did not have the phenotype.
Case 4 - FF – Presented with developmental delay, deficits in social function, sensory sensitivity, and seizures. A microarray showed a copy number variant characterized by a triplication involving chromosomal region 15q11.1q13.2 and duplication involving chromosomal region 15q13.2q13.3. Both mom and dad tested negative for chromosomal abnormality.
Conclusion:
The patients reported had various sizes of microdeletion and microduplication and yet shared a neurodevelopmental phenotype characterized by varying degrees of impaired executive function, emotional regulation, cognition, learning and social adaptation. This shared phenotype has been observed in certain neurodevelopmental disorders including ASD, ADHD, SD, fragile X syndrome, and fetal alcohol spectrum disorder. This suggests that the genes affected in these chromosomal abnormalities are involved in a common etiopathogenic endophenotype. Four OMIM morbid genes found in the 15d11.2 copy number variation region have been functionally associated with neurodevelopmental disorders mentioned above. Further characterization of the functional relationships could lead to the development of a common treatment strategy for several neurodevelopmental disorders.