A novel maternally‐derived insertional translocation resulting in partial trisomy 4q13.2–q22.1 with complex translocation t(8;20) in a family with intellectual disability

Abstract

We characterized the chromosomal aberration in family with intellectual disability, including two affected children and their affected mother. Initial standard karyotypes of the three individuals showed an apparently balanced translocation of chromosomes 8 and 20. Using molecular cytogenetic techniques, we observed complex structural chromosomal aberration comprising of reciprocal translocation between chromosomes 8 and 20 with pericentric inversion (8p11.12q22.3) and insertion of chromosome 4 segments into both der(8) and der(20). In particular, the insertion of chromosome 4 was complex. Two segments (4q13.2-q13.3 and 4q21.21-q22.1) were inserted into the der(8)t(8;20) breakpoint and one segment (4q13.3-q21.21) into the der(20)t(8;20) breakpoint. Both children inherited two normal chromosomes 4 from their parents and the der(8) and der(20) from the mother, resulting in partial trisomy of 4q13.2-q22.1. Interestingly, the mother, in addition to the same complex insertions and inversion, was founded to have a deletion of 4q13.2-q22.1 in one of her chromosomes 4, yielding no genetic imbalance but with potential disruption of intellectual dysfunction-related gene(s) at the breakpoints as the cause of her intellectual impairment. This family is the third case report of an insertional translocation mechanism causing partial trisomy 4q syndrome. Our study demonstrates that an insertion of an extra chromosomal segment, not primarily involving in translocation breakpoints, which results in partial trisomy, can be an unapparent cause of the abnormal phenotypes.

Partial trisomy of 11q23.3‐q25 inherited from a maternal low‐level mosaic unbalanced translocation

“…Common segmental aneusomies result from deletion, duplication, triplication, terminal translocation, and insertional translocation [Kang et al, ; Assawamakin et al, ; Thierry et al, ]. Our patient showed segmental trisomy of 11q23.3‐q25 with no copy number changes in another chromosome.…”

Interstitial microdeletions including the chromosome band 4q13.2 and the UBA6 gene as possible causes of intellectual disability and behavior disorder

“…To the best of our knowledge, the proximal 4q chromosomal aberrations identified in patients with neurodevelopmental phenotypes are rare, non recurrent, heterogeneous in size (usually affecting several megabases of sequence) and breakpoints and, in consequence, involve different chromosome bands and a high number of genes [Zollino et al, ; Nowaczyk et al, ; Shashi et al, ; Eggermann et al, ; Bonnet et al, ; Lipska et al, ; Assawamakin et al, ; Girirajan et al, ; Matoso et al, ; Shimada et al, ; Hemati et al, 2014; Utine et al, ]. Amongst these alterations we can distinguish chromosomal aberrations restricted to 4q13 chromosome bands [Girirajan et al, ; Matoso et al, ; Shimada et al, ] (Table ), as those of our patients, from larger alterations involving additional chromosome bands [Zollino et al, ; Nowaczyk et al, ; Shashi et al, ; Eggermann et al, ; Bonnet et al, ; Lipska et al, ; Assawamakin et al, ; Hemati et al, 2014; Utine et al, ]. Figure is an schematic overview of the proximal 4q region showing the SNP array results in our patients, previously reported chromosomal alterations restricted to 4q13 chromosome bands and OMIM‐morbidity and candidate genes implicated in this interval (Fig.…”

“…In that sense, Assawamakin et al [] have recently described a family with ID and a maternally derived complex structural variation resulting in partial trisomy 4q13.2‐q22.1 with a complex translocation t(8;20) in two affected siblings with ID. Their mother, also with cognitive impairment, carried the same complex chromosomal aberration present in her children but in combination with a heterozygous 4q13.2‐q22.1 deletion, resulting in no copy number change in this region.…”

“…To date, few clinical descriptions of patients with neurodevelopmental phenotypes and proximal 4q chromosomal aberrations have been reported. All of them are variable in type (both copy number losses and gains as well as complex rearrangements), size (ranging from ∼1,5 Mb to ∼25 Mb) and breakpoints and encompass different chromosome bands (restricted to 4q13 or expanding into adjacent chromosome bands) and genes [Zollino et al, ; Nowaczyk et al, ; Shashi et al, ; Eggermann et al, ; Bonnet et al, ; Lipska et al, ; Assawamakin et al, ; Girirajan et al, ; Matoso et al, ; Shimada et al, ; Hemati et al, 2014; Utine et al, ]. So that, the interpretation of their clinical implications, the discovery of candidate genes and the establishment of genotype–phenotype correlations are challenging tasks that remain to be addressed.…”

Pathologic Genomic Rearrangements in Idiopathic Mentally Retarded Patients from Iran

“…Of the more than 90 genes that may be deleted in 22q13.3 deletion syndrome (Phelan-McDermid syndrome), the majority of the neurological features are thought to be caused by haploinsufficiency of SHANK3 [22] which is deleted in patient 3 too. 4q duplication is a rare condition that usually presents with MR and multiple abnormalities, including microcephaly, malformed ears, flat nasal bridge, tooth and thumb anomalies [23,24], most of which are shared by patient 4.…”