Novel multilocus imprinting disturbances in a child with expressive language delay and intellectual disability.

ABSTRACT

Multilocus imprinting disturbances (MLID) have been associated with up to 12% of patients with Beckwith-Wiedemann syndrome, Silver-Russell syndrome, and pseudohypoparathyroidism type 1B (PHP1B). Single-gene defects affecting components of the subcortical maternal complex (SCMC) have been reported in cases with multilocus hypomethylation defects. We present a patient with speech and language impairment with mild Angelman syndrome (AS) features who demonstrates maternal hypomethylation at 15q11.2 (SNRPN) as well as 11p15.5 (KCNQ1OT1) imprinted loci, but normal methylation at 6q24.2 (PLAGL1), 7p12.1 (GRB10), 7q32.2 (MEST), 11p15.5 (H19), 14q32.2 (MEG3), 19q13.43 (PEG3), and 20q13.32 (GNAS and GNAS-AS1). The proband also has no copy number nor sequence variants within the AS imprinting center or in UBE3A. Maternal targeted next generation sequencing did not identify any pathogenic variants in ZPF57, NLRP2, NLRP5, NLRP7, KHDC3L, PADI6, TLE6, OOEP, UHRF1 or ZAR1. The presence of very delayed, yet functional speech, behavioral difficulties, EEG abnormalities but without clinical seizures, and normocephaly are consistent with the 15q11.2 hypomethylation defect observed in this patient. To our knowledge, this is the first report of MLID in a patient with mild, likely mosaic, Angelman syndrome.