Copy Number Variation in Proximal Chromosome 15q11.2

Genome studies have unveiled an important role for copy number variation (CNV) in shaping the normal human genetic landscape. At the extreme of CNV, genomic disorders arise from deletion or duplication of dosage-sensitive genes. Genomic disorders and many CNV appear to have endpoints associated with segmental duplications (SDs). In proximal chromosome 15, several SD regions flank unique DNA sequences containing genes creating a highly unstable environment leading to frequent rearrangements and resulting in genomic disorders, including Prader-Willi and Angelman syndromes, autism, mental retardation and seizure disorders, and schizophrenia.

Multiple breakpoint (BP) hotspots contain the rearrangement endpoints of 15q11-q13 genomic disorders. This investigation focuses on a population study the frequency of CNV in proximal 15q11.2, involving BP1 and BP2 flanking a unique DNA segment with four conserved and functional genes. From a population of 3,503 normal individuals studied by oligonucleotide (ON)-arrays, Q-PCR and smaller published datasets, we determined the frequency of BP1-BP2 deletion (0.91 percent) and duplication (0.37 percent) CNV. Similar frequencies occur for BP1-BP2 deletion (0.66 percent) and duplication (0.57 percent) CNV in a clinical population of 9,387 patients with mental retardation and/or multiple congenital anomalies, studied using BAC and ON-arrays, including smaller published datasets.

In patients, the CNV was inherited from an unaffected parent in all examined cases. The equivalent frequencies and Mendelian heritability observed in normal and clinical populations indicate that most BP1-BP2 CNV are not linked to disease and represent copy number polymorphism. Nevertheless, BP1-BP2 CNV could unmask recessive mutations and/or represent disease susceptibility alleles due to gene dosage alterations and interaction with other genetic loci. Moreover, CNV in such unstable genomic regions could predispose to further instability leading to genomic disorders in offspring.

Principal Investigator
Robert Nicholls, PhD

Last Update
August 14, 2010
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Last Update
August 14, 2010