27 - Rare Focal Deletions Involving SNRPN and UBE3A Genes

Abstract

Prader-Willi (PWS) and Angelman (AS) syndromes are genetic disorders with multiple well-known mechanisms. Approximately 70% of individuals with PWS or AS have a ~4 Mb deletion of 15q11-q13, while the remainder have UPD15, an imprinting defect or, in the case of UBE3A, a sequence variant. Rarely have focal deletions been reported. We report here on three such unusual cases from our clinical microarray experience. Case 1 was a 2-1/2 year old boy with global developmental delay, short stature, microcephaly, failure to thrive and possible hearing loss. This boy, his healthy mother and maternal grandfather had a 36 kb deletion involving only noncoding exons 1 and 2 of UBE3A (NM_130839). Although previously unreported, this deletion is considered likely pathogenic based upon the AS phenotype in the proband and the inheritance pattern in this family. Case 2 was a 2-1/2 year old girl with epilepsy referred for testing on our childhood epilepsy panel which includes sequencing and copy number analysis of 58 relevant genes. Exon-level array showed an intragenic deletion of exons 2–4 of UBE3A. Methylation -specific MLPA (MS-MLPA) showed normal imprinting. Parental testing may be informative in assisting diagnosis since only maternal inheritance would be consistent with AS. Case 3 was the phenotypically normal father of a boy with PWS and a known SNRPN deletion. Array showed that the father had a 109 kb deletion of exons 4–12 of SNRPN (NM_022808) as well as the upstream reading frame (SNURF). MS-MLPA showed that this deletion was on the maternally derived chromosome. Although rare, intragenic or gene deletion of either UBE3A or SNRPN rather than the common 4 Mb deletion can be observed with PWS and AS. An assay which provides exon level coverage of these genes is important when interrogating this region.