Abstract
BackgroundThe 15q11-q13 region contains many low copy repeats and is well known for its genomic instability. Several syndromes are associated with genomic imbalance or copy-number-neutral uniparental disomy. We report on two patients: Patient 1 is a boy with developmental delay and autism; and Patient 2 is a girl with developmental delay, hypotonia and dysmorphism. We performed analyses to delineate their dosage in the 15q region, determine whether the patients’ dosage correlates with phenotypic severity, and whether genes in the amplified regions are significantly associated with identified functional networks.ResultsFor the proximal region of 15q, molecular cytogenetic analysis with Agilent oligonucleotide array showed a copy number of 3 for Patient 1 and a copy number of 4 for Patient 2. Fluorescent in situ hybridization analysis of Patient 2 showed two different populations of cells with different marker chromosomes. Methylation analysis of the amplified region showed that the extra copies of small nuclear ribonucleoprotein polypeptide N gene were of maternal origin. Phenotypic severity did not correlate with the size and dosage of 15q, or whether the amplification is interstitial or in the form of a supernumerary marker. Pathway analysis showed that in Patient 2, the main functional networks that are affected by the genes from the duplicated/triplicated regions are developmental disorder, neurological disease and hereditary disease.ConclusionsThe 15q11-q13 gains that were found in both patients could explain their phenotypic presentations. This report expands the cohort of patients for which 15q11-q13 duplications are molecularly characterized.
Highlights
The 15q11-q13 region contains many low copy repeats and is well known for its genomic instability
Genomic disorders mapped to this region include Angelman syndrome (Online Mendelian Inheritance in Man (OMIM) #105830) and Prader-Willi syndrome (OMIM #176270)
Fluorescent in situ hybridization (FISH) analysis showed two centromeric 15 signals (D15Z1) and two signals localized to Small nuclear ribonucleoprotein polypeptide N (SNRPN) on this marker chromosome (Figure 1A)
Summary
The 15q11-q13 region contains many low copy repeats and is well known for its genomic instability. Several syndromes are associated with genomic imbalance or copy-number-neutral uniparental disomy. Several breakpoint (BP) regions have clusters that contain low copy repeats and segmental duplications [1]. In the majority of cases, both of the syndromes are due to either deletion or uniparental disomy. Of the remaining cases of Angelman syndrome, approximately 10-15% are due to UBE3A mutations and 2-4% are due to imprinting centre defect. Less than 1% of the remaining Prader-Willi syndrome cases are due to imprinting centre defect [3]. The high frequency of such cases gave rise to a clinically recognizable disorder called 15q duplication syndrome, with some common neurobehavioural phenotypes [4]. Four, five and six have all been reported for this region [5,6,7]
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