Microdeletion of the 15q11.2 BP1-BP2 region, also known as Burnside-Butler susceptibility region, is associated with phenotypes like delayed developmental language abilities along with motor skill disabilities, combined with behavioral and emotional problems. The 15q11.2 microdeletion region harbors four evolutionarily conserved and non-imprinted protein-coding genes: NIPA1, NIPA2, CYFIP1, and TUBGCP5. This microdeletion is a rare copy number variation frequently associated with several pathogenic conditions in humans. The aim of this study is to investigate the RNA-binding proteins binding with the four genes present in 15q11.2 BP1-BP2 microdeletion region. The results of this study will help to better understand the molecular intricacies of the Burnside-Butler Syndrome and also the possible involvement of these interactions in the disease aetiology. Our results of enhanced crosslinking and immunoprecipitation data analysis indicate that most of the RBPs interacting with the 15q11.2 region are involved in the post-transcriptional regulation of the concerned genes. The RBPs binding to this region are found from the in silico analysis, and the interaction of RBPs like FASTKD2 and EFTUD2 with exon-intron junction sequence of CYFIP1 and TUBGCP5 has also been validated by combined EMSA and western blotting experiment. The exon-intron junction binding nature of these proteins suggests their potential involvement in splicing process. This study may help to understand the intricate relationship of RBPs with mRNAs within this region, along with their functional significance in normal development, and lack thereof, in neurodevelopmental disorders. This understanding will help in the formulation of better therapeutic approaches.

Prenatal genetic counseling of fetuses diagnosed with 15q11.2 copy number variants (CNVs) involving the BP1-BP2 region is difficult due to limited information and controversial opinion on prognosis. In total, we collected the data of 36 pregnant women who underwent prenatal microarray analysis from 2010 to 2017 and were assessed at National Taiwan University Hospital. Comparison of the maternal characteristics, prenatal ultrasound findings, and postnatal outcomes among the different cases involving the 15q11.2 BP1-BP2 region were presented. Out of the 36 fetuses diagnosed with CNVs involving the BP1-BP2 region, five were diagnosed with microduplications and 31 with microdeletions. Among the participants, 10 pregnant women received termination of pregnancy and 26 gave birth to healthy individuals (27 babies in total). The prognoses of 15q11.2 CNVs were controversial and recent studies have revealed its low pathogenicity. In our study, the prenatal abnormal ultrasound findings were recorded in 12 participants and were associated with 15q11.2 deletions. No obvious developmental delay or neurological disorders were detected in early childhood.

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Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, \'de novo\' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.