Copy number variation (CNV) analysis and mutation analysis of the 6q14.1-6q16.3 genes SIM1 and MRAP2 in Prader Willi like patients.

BACKGROUND: Prader-Willi syndrome (PWS), caused by a paternal defect on 15q11.2-q13, is the most common form of syndromic obesity. However, patients clinically diagnosed with PWS do not always show this defect on chromosome 15q and are therefore molecularly categorized as Prader Willi like (PWL). Deletions at 6q14.1-q16.3 encompassing MRAP2 and SIM1 were reported in some individuals with a PWL phenotype. In addition, a few mutations in SIM1 and MRAP2 were also previously identified in cohorts of obese individuals. Therefore, we decided to perform copy number variation analysis of the 6q14.1-6q16.3 region followed by mutation analysis of SIM1 and MRAP2 in a PWL cohort.

METHODS: A genome-wide microarray analysis was performed in a group of 109 PWL patients. Next, we screened 94 PWL patients for mutations in SIM1 and MRAP2 using high-resolution melting curve analysis and Sanger sequencing. Additionally, 363 obese children and adolescents were screened for mutations in MRAP2.

RESULTS: No gene harboring deletions were identified at the 6q14.1-q16.3 region in the 109 PWL patients. SIM1 mutation analysis resulted in the identification of one very rare nonsynonymous variant p.P352S (rs3734354). Another rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene. No variants were identified in the 363 obese individuals.

CONCLUSIONS: In contrast to literature reports, no gene harboring deletions were identified in the SIM1 and MRAP2 regions in our PWL cohort. Secondly, taking into account their very low minor allele frequencies in public sequencing databases and the results of in silico prediction programs, further functional analysis of p.P352S found in SIM1 and p.A40S found in MRAP2 is useful. This would provide further support for a possible role of SIM1 and MRAP2 in the pathogenesis of the PWL phenotype albeit in a limited number of patients.