Neurodevelopmental features in 2q23.1 microdeletion syndrome: Report of a new patient with intractable seizures and review of literature

Abstract

2q23.1 microdeletion syndrome is a recently characterized chromosomal aberration disorder uncovered through array comparative genomic hybridization (array CGH). Although the cardinal feature is intellectual disability (ID), neurodevelopmental features of the syndrome have not been systematically reviewed. We present a 5-year-old boy with severe psychomotor developmental delay/ID, progressive microcephaly with brain atrophy, growth retardation, and several external anomalies. He manifested intractable epilepsy, effectively treated with combined antiepileptic drug therapy including topiramate. Array CGH demonstrated a de novo interstitial deletion of approximately 1 Mb at 2q23.1-q23.2, involving four genes including MBD5. Nineteen patients have been reported to have the syndrome, including present patient. All patients whose data were available had ID, 17 patients (89%) had seizures, and microcephaly was evident in 9 of 18 patients (50%). Deletion sizes ranged from 200 kb to 5.5 Mb, comprising 1-15 genes. MBD5, the only gene deleted in all patients, is considered to be responsible for ID and epilepsy. Furthermore, the deletion junction was sequenced for the first time in a patient with the syndrome; and homology of three nucleotides, identified at the distal and proximal breakpoints, suggested that the deletion might have been mediated by recently-delineated genomic rearrangement mechanism Fork Stalling and Template Switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR).

Clinical and Molecular Aspects of MBD5-Associated Neurodevelopmental Disorder (MAND)

“…16,17 It has been suggested that 2q23.1 deletions could be deletion mediated by recently delineated genomic rearrangement mechanism Fork Stalling and Template Switching (FoSTeS)/microhomologymediated break-induced replication (MMBIR). 9 Upon aligning the 65 deletion regions, the study found that the smallest region of overlap (SRO) was defined to one gene, MBD5. 2 Single asterisks indicate cases known to be de novo.…”

Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities

“…A multi-institution collaboration of clinical diagnostic laboratories resulted in inclusion of additional patients not previously published from the Greenwood Genetic Center (Cases 9–12), Pathology Associates Medical Laboratories (Cases 13–14), Virginia Commonwealth University (Case 15), Fullerton Genetics Center (Case 16), and Boston Children’s Hospital (Case 17) that were identified with different cytogenomic microarray platforms. Phenotypes were further considered in the analysis of two MBD5 deletion cases reported by Motobayashi et al 19 (Motobayashi/Case 18) and Noh et al 20 (Noh/Case 19) as well an intragenic frameshift mutation c.150del or p.Thr52Hisfs*31 described by Kleefstra et al 5 (Kleefstra/Case 20) and an intragenic indel of -TC at position 148,942,435 in hg18 of exon 9 described by O’Roak et al 21 (O’Roak/Case 21), all of which were published after the Talkowski et al study 6 . The final patient, DGAP235 (Case 22), was enrolled in the Developmental Genome Anatomy Project (DGAP; www.dgap/harvard.edu) based on karyotypic detection of a de novo , balanced translocation 46,XY,t(2;5)(q22;q22), which was found to disrupt MBD5 by massively parallel paired-end sequencing; this case was independent of two previously published translocations targeting MBD5 .…”

Disorders and borders: Psychiatric genetics and nosology

“…ASD: autism spectrum disorders; ID/DD: intellectual disability/developmental delay; SCZ: schizophrenia; ADHD: attention deficit/hyperactivity disorder. Del: deletion; Dup: duplication [Vrijenhoek et al, ; Helbig et al, ; Niklasson et al, ; Shinawi et al, ; de Kovel et al, ; Cooper et al, ; Levinson et al, ; Lionel et al, ; Philip and Bassett, ; Sanders et al, ; Talkowski et al, ; Crespi and Crofts, ; Malhotra and Sebat, ; Motobayashi et al, ; Schaaf et al, ; Williams et al, ; Bena et al, ; Girirajan et al, ; Moller et al, ; Vorstman et al, ].…”