Expanding the clinico-molecular spectrum of Angelman syndrome phenotype with the GABRG3 gene: Evidence from methylation and sequencing studies.

Angelman syndrome (AS) (OMIM#105830) is an imprinting disorder caused due to alterations in the maternal chr 15q11-13 region. Majority of cases can be diagnosed by methylation-specific polymerase chain reaction (MS-PCR) of SNRPN gene and by UBE3A sequencing, however, about 10% of cases with AS phenotype remain undiagnosed. Differential diagnoses of AS can be detected by chromosomal microarray (CMA) and clinical exome sequencing (CES). In this study, 30 cases with AS features were evaluated by MS-PCR, CMA, and CES. SNRPN MS-PCR confirmed AS in eight (26%), CMA and CES diagnosed nine (30%) cases. One case was identified with a novel variant c.1125C > T in GABRG3, located at 15q12 region, which is currently not associated with any syndrome. The GABRG3 gene is also speculated to be imprinted, a MS-PCR assay was designed to confirm its differential parental methylation status. This assay identified another case with altered GABRG3 methylation. The two cases with GABRG3 alteration-sequence change and methylation indicate that GABRG3 may be associated with a subtype of AS or a new related syndrome. Performing GABRG3 MS-PCR and sequencing of a larger group of patients with AS phenotype and normal SNPRN and UBE3A status will help in establishing exact genotype-phenotype correlation.