Partial duplication of 4q12q13 leads to a mild phenotype

Abstract

We report on the second case of duplication (4)(q12q13) with microcephaly, mental retardation, and minor facial anomalies. Duplications involving the distal region of chromosome 4q are well described and share common clinical findings. However, phenotypic abnormalities of duplications of the proximal portion of chromosome 4q are relatively unknown. A comparison of the clinical manifestations of our patient and the single published case suggests that the phenotype of this proximal 4q duplication is relatively mild. This study emphasizes the need to perform chromosome analysis in similar mildly affected/nonspecific cases.

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

“…Larger deletions, with partial or total overlap with those identified in our patients, include a 4q13.2‐q21.22 deletion [Eggermann et al, ], a large deletion of approximately 18 Mb detected at 4q13.1q21.21 [Utine et al, ], as well as non‐ recurrent interstitial deletions with breakpoints in 4q12 and expanding different chromosome bands [Hemati et al, 2014]. Earlier reports have also identified large alterations affecting the proximal 4q region, but no detailed definition at a molecular level was provided since they were detected with conventional techniques [Zollino et al, ; Nowaczyk et al, ; Shashi et al, ] and will not be discussed in this paper.…”

“…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.…”

“…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.…”

Insertional translocation leading to a 4q13 duplication including theEPHA5gene in two siblings with attention‐deficit hyperactivity disorder

“…Constitutional proximal duplications of 4q have been described rarely [Mattei et al, ; Shashi et al, ; Zollino et al, ; Bonnet et al, ]. Probably given a mild phenotype, without any malformations or growth retardation, duplications of this segment can go unnoticed.…”

The Hand2 Gene Dosage Effect in Developmental Defects and Human Congenital Disorders

“…Duplication of the distal end of the long arm of human chromosome 4, which includes 4q34, leads to the congenital disorder, "Partial trisomy distal 4q" (denoted 4q +), whose typical phenotypes include growth retardation, psychomotor retardation, microcephaly, epicantic folds, high nasal bridge, short philtrum, micrognathia, low set/malformed ear, preaxial polydactyly, epilepsy, renal hypoplasia, and congenital heart disease (Battaglia et al, 2005;Lundin, Zech, Sj€ ors, Wadelius, & Annerén, 2002;Lurie, 2005;Rinaldi et al, 2003). Furthermore, patients with the pure 4q duplication, who could provide the key to identifying the causative gene, are very rare (Celle et al, 2000;Goodman, Capone, Hennessey, & Thomas, 1997;Jeziorowska et al, 1993;Mikelsaar, Lurie, & Ilus, 1996;Shashi, Berry, Santos, & Pettenati, 1999;Vogel, Siebers, & Gunkel, 1975;Zollino, Zampino, Torrioli, Pomponi, & Neri, 1995). However, causative gene(s) of each phenotype have remained unclear.…”