FISH and array‐CGH analysis of a complex chromosome 3 aberration suggests that loss of CNTN4 and CRBN contributes to mental retardation in 3pter deletions

Abstract

Imbalances of 3p telomeric sequences cause 3p- and trisomy 3p syndrome, respectively, showing distinct, but also shared clinical features. No causative genes have been identified in trisomy 3p patients, but for the 3p- syndrome, there is growing evidence that monosomy for one or more of four genes at 3pter, CHL1, CNTN4, CRBN, and MEGAP/srGAP3, may play a causative role. We describe here an analysis of a complex chromosome 3p aberration in a severely mentally retarded patient that revealed two adjacent segments with different copy number gains and a distal deletion. The deletion in this patient included the loci for CHL1, CNTN4, and CRBN, and narrowed the critical segment associated with the 3p- syndrome to 1.5 Mb, including the loci for CNTN4 and CRBN. We speculate that the deletion contributes more to this patient's phenotype than the gains that were observed. We suggest that 3p- syndrome associated features are primarily caused by loss of CNTN4 and CRBN, with loss of CHL1 probably having an additional detrimental effect on the cognitive functioning of the present patient.

Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system

“…Like APP, contactin 4 and L1CAM are implicated in neurological disorders. Contactin 4 gene disruption is proposed to cause 3p deletion syndrome, involving mental retardation (Fernandez et al, 2004;Dijkhuizen et al, 2006). Mutations in L1CAM cause CRASH syndrome, which includes mental retardation and corpus callosum hypoplasia (Fransen et al, 1995).…”

Clinical characterization of a Korean case with 3p25 deletion

“…There is growing evidence that haploinsufficiency of four genes at chromosome 3pter, CHL1 (MIM*607416), CNTN4 (MIM*607280), CRBN (MIM*609262), and SRGAP3 (MIM*606525), may play an important role in the cognitive impairment associated with this syndrome [2,10,17]. The CNTN4 gene encodes a neuronal adhesion molecule that is involved in axonal growth, guidance, fasciculation, and synaptic plasticity [18].…”

“…Genomic alterations in the telomeric region of the short arm of chromosome 3 (3p) are associated with two major syndromes: 3p deletion and 3p trisomy syndrome [1,2]. Both syndromes are clinically characterized by various types of dysmorphisms and mental or cognitive retardation [2].…”

“…Both syndromes are clinically characterized by various types of dysmorphisms and mental or cognitive retardation [2].…”

A Subtle Familial Translocation t(3;21)(p26.3;q22.3): An Apparently Healthy Boy with a 3p Deletion and 21q Duplication

“…The distal 3p deletion syndrome is reported with a recognizable phenotype, including developmental delay, low birth weight, growth retardation and several dysmorphic features [Malmgren et al, 2007;Barber et al, 2008;Fernandez et al, 2008]. The critical region was defined as a 1.5 Mb region on chromosome 3p26, containing the candidate genes CHL1, CNTN4 and CRBN [Cargile et al, 2002;Dijkhuizen et al, 2006]. The genes CHL1 and CNTN4 map within the brother's deletion excluding haploinsufficiency of these genes as a cause for MR.…”