|1||Am. J. Med. Genet. A 2013 Nov 161A: 2846-54|
|Title||Genetic counseling for susceptibility loci and neurodevelopmental disorders: the del15q11.2 as an example.|
|Abstract||In recent years, several recurrent copy number variations (CNVs) that confer risk of neurodevelopmental disorders have been identified (e.g., del and dup 16p11.2, del15q13.3, del and dup 1q21.1, del16p13.3, del15q11.2). They are often inherited from an unaffected parent and lack phenotypic specificity. Although there is growing evidence from association studies to consider them as susceptibility CNVs, their clinical utility is debated. Yet the clinician is frequently challenged to deal with these counseling situations without guidelines or consensus. In this report, counseling issues and research opportunities are discussed, with the recurrent 15q11.2 BP1-BP2 (including CYFIP1, NIPA1, NIPA2, TUBGCP5) as an example. Several clinical reports have been published describing patients with del15q11.2 featuring intellectual disability, developmental delay, neurological problems, autism spectrum disorder (ASD), attention problems, speech delay, and dysmorphism. The del15q11.2 was found to be significantly associated with intellectual disability, schizophrenia, epilepsy, and ASD. In this report we discuss how patient-specific and family-specific information may alter the interpretation of del15q11.2 as a contributing factor to the disorder in practical counseling situations. In addition, an association study for ASD in a Belgian Flemish cohort and an overview of reported association studies, clinical reports and genomics data for del15q11.2 are presented.|
|2||Schizophr Bull 2013 May 39: 712-9|
|Title||Rare CNVs and tag SNPs at 15q11.2 are associated with schizophrenia in the Han Chinese population.|
|Abstract||Rare copy number variations (CNVs) were involved in the etiology of neuropsychiatric disorders, and some of them appeared to be shared risk factors for several different diseases. One of those promising loci is the CNV at 15q11.2, including 4 genes, TUBGCP5, CYFIP1, NIPA2, and NIPA1. Several studies showed that microdeletions at this locus were significant associated with schizophrenia. In the current study, we investigated the role of both rare CNVs and common single nucleotide polymorphisms (SNPs) at 15q11.2 in schizophrenia in the Chinese Han population.|
We screened deletions at 15q11.2 in 2058 schizophrenia patients and 3275 normal controls in Chinese Han population by Affymetrix 500K/6.0 SNP arrays and SYBR green real-time polymerase chain reaction and then validated deletions by multiplex ligation-dependent probe amplification and Taqman real-time assays. We successfully genotyped 27 tag SNPs in total and tested associations in 1144 schizophrenia cases and 1144 normal controls.
We found a triple increase of deletions in cases over controls, with OR=4.45 (95% CI=1.36-14.60) and P=.014. In the analysis of common SNPs, we found that the most significant SNP in schizophrenia was rs4778334 (OR=.72, 95% CI=0.60-0.87, allelic P=.0056 after permutation, genotypic P=.015 after permutation). We also found SNP rs1009153 in CYFIP1 was associated with schizophrenia (OR=0.82, 95% CI=0.73-0.93, allelic P=.044 after permutation).
We found that both rare deletions and common variants at 15q11.2 were associated with schizophrenia in the Chinese Han population.
|3||Am. J. Med. Genet. A 2014 Aug 164A: 1916-22|
|Title||Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: further delineation of an emerging syndrome.|
|Abstract||15q11.2 deletions flanked by BP1 and BP2 of the Prader-Willi/Angelman syndrome region have recently been linked to a range of neurodevelopment disorders including intellectual disability, speech and language delay, motor delay, autism spectrum disorders, epilepsy, and schizophrenia. Array CGH analysis of 14,605 patients referred for diagnostic cytogenetic testing found that 83 patients (0.57%) carried the 15q11.2(BP1-BP2) deletion. Phenotypic frequencies in the deleted cohort (n?=?83) were compared with frequencies in the non-deleted cohort (n?=?14,522); developmental delay, motor delay, and speech and language delay were all more prevalent in the deleted cohort. Notably, motor delay was significantly more common (OR?=?6.37). These data indicate that developmental delay, motor delay, and speech and language delay are common clinical features associated with this deletion, providing substantial evidence to support this CNV as a susceptibility locus for a spectrum of neurodevelopmental disorders. © 2014 Wiley Periodicals, Inc.|
|4||Mol Neuropsychiatry 2015 Jul 1: 116-123|
|Title||Genetic and morphological features of human iPSC-derived neurons with chromosome 15q11.2 (BP1-BP2) deletions.|
|Abstract||Copy number variation on chromosome 15q11.2 (BP1-BP2) causes deletion of CYFIP1, NIPA1, NIPA2 and TUBGCP5; it also affects brain structure and elevates risk for several neurodevelopmental disorders that are associated with dendritic spine abnormalities. In rodents, altered cyfip1 expression changes dendritic spine morphology, motivating analyses of human neuronal cells derived from iPSCs (iPSC-neurons).|
iPSCs were generated from a mother and her offspring, both carrying the 15q11.2 (BP1-BP2) deletion, and a non-deletion control. Gene expression in the deletion region was estimated using quantitative real-time PCR assays. Neural progenitor cells (NPCs) and iPSC-neurons were characterized using immunocytochemistry.
CYFIP1, NIPA1, NIPA2 and TUBGCP5 gene expression was lower in iPSCs, NPCs and iPSC-neurons from the mother and her offspring in relation to control cells. CYFIP1 and PSD95 protein levels were lower in iPSC-neurons derived from the CNV bearing individuals using Western blot analysis. At 10 weeks post-differentiation, iPSC-neurons appeared to show dendritic spines and qualitative analysis suggested that dendritic morphology was altered in 15q11.2 deletion subjects compared with control cells.
The 15q11.2 (BP1-BP2) deletion is associated with reduced expression of four genes in iPSC-derived neuronal cells; it may also be associated altered iPSC-neuron dendritic morphology.
|5||Int J Mol Sci 2015 -1 16: 4068-82|
|Title||The 15q11.2 BP1-BP2 microdeletion syndrome: a review.|
|Abstract||Patients with the 15q11.2 BP1-BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen. The 15q11.2 BP1-BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%-1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls. Review of clinical features from about 200 individuals were grouped into five categories and included developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores ?75 (50%); general behavioral problems, unspecified (55%) and abnormal brain imaging (43%). Other clinical features noted but not considered as common were seizures/epilepsy (26%), autism spectrum disorder (27%), attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%). Not all individuals with the deletion are clinically affected, yet the collection of findings appear to share biological pathways and presumed genetic mechanisms. Neuropsychiatric and behavior disturbances and mild dysmorphic features are associated with genomic imbalances of the 15q11.2 BP1-BP2 region, including microdeletions, but with an apparent incomplete penetrance and variable expressivity.|