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

Marwan K Tayeh; Janean DeVaul; Kristin LeSueur; Chen Yang; Jirair K Bedoyan; Peedikayil Thomas; Mark C Hannibal; Jeffrey W Innis

doi:10.1002/ajmg.a.62752

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

Am J Med Genet A. 2022 Jul;188(7):2209-2216. doi: 10.1002/ajmg.a.62752. Epub 2022 Apr 1.

Authors

Marwan K Tayeh¹, Janean DeVaul², Kristin LeSueur², Chen Yang^{2

3}, Jirair K Bedoyan⁴, Peedikayil Thomas⁵, Mark C Hannibal², Jeffrey W Innis^{2

5}

Affiliations

¹ Department of Medical and Molecular Genetics, Division of Indiana, University Genetics Testing Laboratories, Indiana University, Indianapolis, Indiana, USA.
² Department of Pediatrics, Division of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, Ann Arbor, Michigan, USA.
³ Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
⁴ Department of Pediatrics, Division of Genetic and Genomic Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁵ Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

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.

Keywords: maternal hypomethylation; mosaic Angelman syndrome; multilocus imprinting disturbances.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Angelman Syndrome* / diagnosis
Angelman Syndrome* / genetics
Beckwith-Wiedemann Syndrome* / complications
Beckwith-Wiedemann Syndrome* / diagnosis
Beckwith-Wiedemann Syndrome* / genetics
CCAAT-Enhancer-Binding Proteins
Child
DNA Methylation
Genomic Imprinting
Humans
Intellectual Disability* / diagnosis
Intellectual Disability* / genetics
Language Development Disorders* / genetics
Ubiquitin-Protein Ligases

Substances

Adaptor Proteins, Signal Transducing
CCAAT-Enhancer-Binding Proteins
NLRP7 protein, human
UHRF1 protein, human
Ubiquitin-Protein Ligases