De novo microdeletion of 5q14.3 excluding MEF2C in a patient with infantile spasms, microcephaly, and agenesis of the corpus callosum

Abstract

The 5q14.3 microdeletion syndrome has recently been recognized as a clinical entity manifesting as severe intellectual disability, epilepsy, and brain malformations. Analysis of the shortest region of overlap among patients with this syndrome and subsequent identification of nucleotide alterations in the coding region of myocyte enhancer factor 2C gene (MEF2C) have suggested MEF2C as the gene responsible for the 5q14.3 microdeletion syndrome. We identified a de novo 3.4-Mb deletion of 5q14.3 in a patient with infantile spasms, microcephaly, and brain malformation. The deleted region in the present patient was positional toward the centromere, and MEF2C was not included in the deleted region. However the neurological and dysmorphic features of the present patient resembled those of patients with the 5q14.3 microdeletion syndrome. We consider that a positional effect is the likely explanation for this evidence. To study the precise mechanism of this positional effect, further information is required on patients showing atypical deletions neighboring MEF2C.

Brain white matter abnormalities associated with copy number variants

“…An abnormal corpus callosum morphology was seen in 12/13 patients. Corpus callosum dysgenesis has been described in the literature in various CNVs, and has been specifically described in most of our patients' chromosomal microdeletion/microduplication syndromes: 1p36 deletion, 5q14 deletion, 15q13 deletion, 18q21 deletion, 14q32 duplication, Wolf‐Hirschhorm syndrome, 1q43q44 deletion, and 21q22 deletion (Ballif et al, ; Edwards, Sherr, Barkovich, & Richards, ; Gillentine & Schaaf, ; Heide et al, ; Hotz et al, ; Oegema et al, ; Õiglane‐Shlik et al, ; Ramaswamy et al, ; Shimojima et al, ; Verbrugge et al, ; Villa et al, ). A study on the role of chromosomal micro‐rearrangements in patients with both corpus callosum abnormality and intellectual disability, found that 13% had CNVs as the probable cause of their disorder (Heide et al, ).…”

ADGRV1 is implicated in myoclonic epilepsy

“…8,9 A neurocutaneous syndrome involving intracranial and dermatologic vascular malformations has also been described. 4,5,7,[13][14][15] However, MEF2C lies outside the deleted region in at least 5 reported cases of 5q14.3 deletion syndrome, 8,9,16,17 so a role for other genes at the 5q14.3 locus is likely. Current literature points to MEF2C (OMIM 600662) haploinsufficiency playing the most important role, largely based on identification of intragenic mutations of this gene in patients with intellectual disability, stereotypies, and infantile-onset epilepsy, which may include infantile spasms, and myoclonic, atonic, generalized tonicclonic, focal impaired awareness, atypical absence, and hemiclonic seizures.…”

“…Current literature points to MEF2C (OMIM 600662) haploinsufficiency playing the most important role, largely based on identification of intragenic mutations of this gene in patients with intellectual disability, stereotypies, and infantile-onset epilepsy, which may include infantile spasms, and myoclonic, atonic, generalized tonicclonic, focal impaired awareness, atypical absence, and hemiclonic seizures. 4,5,7,[13][14][15] However, MEF2C lies outside the deleted region in at least 5 reported cases of 5q14.3 deletion syndrome, 8,9,16,17 so a role for other genes at the 5q14.3 locus is likely.…”

Infantile spasms in a boy with an abnormal karyotype (46, XY, der(9)t(7;9)(p15;p22)pat)

“…[4] Down's syndrome is the most common chromosomal abnormality reported in patients with IS; however, many other types of chromosomal abnormalities have been reported, including 1p36 deletion, 17p 13.3 microdeletion, 22q, XXY [4] , partial 2p trisomy, 4p trisomy, 7q trisomy, 7q duplication, 15p tetrasomy, 15q duplication, 18p monosomy, 18q duplication, 21 trisomy, t (12;21), t (X; 18)(p22;p11.2), t (6;14)(q27;q13.3), t (1;Y), and disomy for Xq26.3-qter [2,3] , 5q14.3, 7q11.23-q21.1, tetrasomy 12p, 15q13.3, 16p13.11 microdeletion, 17q21.31 microdeletion, and 19p13 deletion. [5][6][7][8] It was once presumed that the chromosomal abnormality, trisomy 7q33->qter and monosomy 9 pter->p23, found in a child was probably the etiology for the IS and multiple anomalies, and the epilepsy is most likely resulted from the distal 7q duplication and not distal 9p deletion. [9] Epilepsy was once associated with chromosome 7 abnormities: Trisomy of the short-arm of chromosome 7 was formerly reported to be associated with epileptic crises [10] and long-arm deletion of chromosome 7 was also previously found to be associated with IS.…”