Reinforcing the association between distal 1q CNVs and structural brain disorder: A case of a complex 1q43‐q44 CNV and a review of the literature

Abstract

Copy Number Variations (CNVs) comprising the distal 1q region 1q43-q44 are associated with neurological impairments, structural brain disorder, and intellectual disability. Here, we report an extremely rare, de novo case of a 1q43-q44 deletion with an adjacent duplication, associated with severe seizures, microcephaly, agenesis of the corpus callosum, and pachygyria, a consequence of defective neuronal migration disorder. We conducted a literature survey to find that our patient is only the second case of such a 1q43-q44 CNV ever to be described. Our data support an association between 1q43-q44 deletions and microcephaly, as well as an association between 1q43-q44 duplications and macrocephaly. We compare and contrast our findings with previous studies reporting on critical 1q43-q44 regions and their constituent genes associated with seizures, microcephaly, and corpus callosum abnormalities [Ballif et al., 2012; Hum Genet 131:145-156; Nagamani et al., 2012; Eur J Hum Genet 20:176-179]. Taken together, our study reinforces the association between 1q43-q44 CNVs and brain disorder.

Familial 3-Way Balanced Translocation Causes 1q43→qter Loss and 10q25.2→qter Gain in a Severely Affected Male Toddler

“…However, just 2 patients exhibited almost identical breakpoints (ISCA patients nssv577258 and nssv577260). In addition, approximately 10 other deletions (DECIPHER patients 2219 and 4092; ISCA patients nssv577264, nssv584387, nssv1415047, nssv13655372, and nssv3396736 as well as patients "Proband", "H1", and "S6" from Hemming et al [2016]) involved comparable breakpoints to those of the present patient (online suppl. Fig.…”

“…Separately, 1qter losses overlapping our patient's partial monosomy are relatively common, as DECIPHER reports 138 cases with deletions ranging from 13 kb to 17.5 Mb in size, and the literature contains approximately 160 other cases of pure and nonpure 1q43q44 deletions [Hemming et al, 2016]. However, just 2 patients exhibited almost identical breakpoints (ISCA patients nssv577258 and nssv577260).…”

“…Among the morbid genes identified in the deleted region in our patient, perhaps the most representative for the 1q43q44 deletion syndrome are AKT3 , ZBTB18 , and HNRNPU , which are related to microcephaly, brain malformations, and seizures, respectively [de Munnik et al, 2014;Hemming et al, 2016]. Significantly, our patient presented with the first 2 features but has not yet suffered from seizures.…”

“…Several other comparable duplications are mostly derived from a translocation and have been described as distal 10q trisomy syndrome [e.g., Bartholdi et al, 2008;Al-Sarraj et al, 2014]. Common and not so common features found in this syndrome and present in our patient include DD/ID, growth retardation, blepharophimosis, flat face, flat nasal bridge, Hemming et al [2016]. e A full description of clinical features is given in the Clinical Report section.…”

“…Although the phenotypes of these patients (our patient included) are rather heterogeneous ( Table 1 ), all of the patients presented with a common core of clinical features consistent with the well-recognized 1q43q44 deletion syndrome (OMIM 612337), including DD/intellectual disability (ID) and brain and cardiac anomalies. The phenotypic inconsistencies among patients are often ascribable to concomitant imbalances or incomplete penetrance and/or variable expressivity of some traits [Hemming et al, 2016]. In fact, at least 4 of these instances (DE-CIPHER patients 2219 and 4092, the proband from Hemming et al [2016], and this case) demonstrated additional imbalances ( Table 1 ).…”