Complex craniosynostosis is associated with the 2p15p16.1 microdeletion syndrome

Abstract

In a screening project of patients with (complex) craniosynostosis using genomic arrays, we identified two patients with craniosynostosis and microcephaly with a deletion in the 2p15p16.1 chromosomal region. This region has been associated with a new microdeletion syndrome, for which patients have various features in common, including microcephaly and intellectual disability. Deletions were identified using Affymetrix 250K SNP array and further characterized by fluorescence in situ hybridization (FISH) analysis and qPCR. The deletions in our two patients overlapped within the 2p15p16.1 microdeletion syndrome area and were 6.8 and 6.9 Mb in size, respectively. FISH and qPCR confirmed the presence of only one copy in this region. Finemapping of the breakpoints indicated precise borders in our patients and were further finemapped in two other previously reported patients. Clinical features of patients with deletions in the 2p15p16.1 region vary. Including data from our patients, now eight out of nine reported patients have microcephaly, one of the major features, and all had intellectual disability. The current reported two patients add different forms of craniosynostosis to the clinical spectrum of this recently recognized microdeletion syndrome.

Brain malformations in a patient with deletion 2p16.1: A refinement of the phenotype to BCL11A

“…Following the initial report in 2007 by Rajcan-Separovic et al [Rajcan-Separovic et al, 2007], there have been 15 patients reported in the literature with overlapping deletions in this region [Chabchoub et al, 2008;Fannemel and Barøy, 2014;Florisson et al, 2013;Félix and Petrin, 2010;Hancarova et al, 2013;Hucthagowder et al, 2012;Liang et al, 2009;Peter et al, 2014;Piccione et al, 2012;Prontera et al, 2011;de Leeuw et al, 2008], in addition to reports from public databases such as DECIPHER and ISCA [Firth et al, 2009;Miller et al, 2010] and other large studies assessing developmental delay and copy number variants [Cooper et al, 2011;Kaminsky et al, 2011]. All of the reported patients had varying degrees of developmental delay, along with shared dysmorphic features and microcephaly, making this a recognizable microdeletion syndrome.…”

“…All of the reported patients had varying degrees of developmental delay, along with shared dysmorphic features and microcephaly, making this a recognizable microdeletion syndrome. Brain imaging findings in these patients suggest the 2p15-16.1 region contains important genes for brain development [Florisson et al, 2013;Hucthagowder et al, 2012;Piccione et al, 2012;Rajcan-Separovic et al, 2007]. Some of the reports of patients with 2p15-16.1 deletion have suggested narrowing the critical region of the neurodevelopmental phenotype to 4 genes; BCL11A, PAPOLG, REL and PEX13 [Hancarova et al, 2013;Liang et al, 2009;Piccione et al, 2012;de Leeuw et al, 2008].…”

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

“…In addition, BCL11A is included in most CNVs reported as the 2p15‐p16.1 microdeletion syndrome (OMIM #612513), characterized by developmental delay, intellectual disability, hypotonia, poor verbal skills, craniofacial and skeletal features, digital anomalies, and fetal hemoglobin persistence (Basak et al, 2015; Funnell et al, 2015). When described, patients with 2p15p16 microdeletion encompassing BCL11A show delayed receptive and expressive language skills (Hancarova et al, 2013; Piccione et al, 2012; Rajcan‐Separovic et al, 2007), language delay (Balci, Sawyer, Davila, Humphreys, & Dyment, 2015; Felix, Petrin, Sanseverino, & Murray, 2010), language restricted to a few single words and signing (Florisson et al, 2013), or absence of language (Florisson et al, 2013; Hucthagowder et al, 2012). Apart from Peter, Matsushita, Oda, and Raskind, (2014), who described a 200 kb 2p15p16.1 deletion encompassing the entire BCL11A gene (plus 50 kb of non‐coding sequence but no other known coding or non‐coding gene) in a patient with mild intellectual disability, childhood apraxia of speech, dysarthria, and oral and motor dyspraxia, language anomalies have not been extensively studied in patients with mutations or microdeletions affecting BCL11A .…”

Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis

“…[1][2][3][4][5][6][7][8], and the existence of nonoverlapping copy number variants (CNVs) within the 2p15p16.1 deletion region complicate efforts to delineate a common critical region for the syndrome. In addition, some studies suggested that The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies.…”

“…regulatory elements (enhancers) in the region could also play a role (7). Nevertheless, several deletions involving individual genes or smaller numbers of genes were reported (2)(3)(4)(5)(8)(9)(10) XPO1 (also known as CRM1) is a nuclear export receptor that exports approximately 200 different cargo molecules (e.g., proteins, rRNA, small nuclear RNA [snRNA], miR, and specific mRNAs) from the nucleus to the cytoplasm.…”