Single gene microdeletions and microduplication of 3p26.3 in three unrelated families: CNTN6 as a new candidate gene for intellectual disability

Abstract

Background: Detection of submicroscopic chromosomal alterations in patients with a idiopathic intellectual disability (ID) allows significant improvement in delineation of the regions of the genome that are associated with brain development and function. However, these chromosomal regions usually contain several protein-coding genes and regulatory elements, complicating the understanding of genotype-phenotype correlations. We report two siblings with ID and an unrelated patient with atypical autism who had 3p26.3 microdeletions and one intellectually disabled patient with a 3p26.3 microduplication encompassing only the CNTN6 gene.

Results: Two 295.1-kb microdeletions and one 766.1-kb microduplication of 3p26.3 involving a single gene, CNTN6, were identified with an Agilent 60K array. Another 271.9-kb microdeletion of 3p26.3 was detected using an Affymetrix CytoScan HD chromosome microarray platform. The CHL1 and CNTN4 genes, although adjacent to the CNTN6 gene, were not affected in either of these patients.

Conclusions: The protein encoded by CNTN6 is a member of the immunoglobulin superfamily and functions as a cell adhesion molecule that is involved in the formation of axon connections in the developing nervous system. Our results indicate that CNTN6 may be a candidate gene for ID.

Keywords: 3p26.3 microdeletion; 3p26.3 microduplication; CNTN6; Intellectual disability; Reciprocal microdeletions/microduplications.

Figure 1

Analysis of the siblings from family F. ( A ) The male patient F (note the tower skull, frontal bossing, antimongoloid slant, epicanthus, wide nasal bridge, large nose, anteverted nostrils, and low-set ears). ( B ) The pedigree plot for family F; the solid square and circle represent the affected siblings. ( C ) The female patient F (note the microcephaly, long face, epicanthus, wide nasal bridge, and short philtrum). ( D ) The CNTN6 deletion in the male patient F. ( E ) Real-time PCR analysis of CHL1, CNTN6, and CNTN4, which revealed two copies of CHL1, a deletion of CNTN6, and two copies of CNTN4 in both patients, respectively. ( F ) The CNTN6 deletion in the female patient F.

Figure 2

Analysis of family N. ( A ) The CNTN6 deletion in patient N. ( B ) Real-time PCR analysis of CNTN6: C1 - female control, C2 - male control, II-1 - patient N, I-1 - mother, I-2 - father; CNTN6_E22a and CNTN6_E22b - probes for exon 22, CNTN6_E23 - probe for exon 23. ( C ) The pedigree plot for family N; the dark, solid circle represents the affected patient N, and the gray, solid square represents father N.

Figure 3

Analysis of family K. ( A ) Patient K (note the dolichocephalic skull, upslanting palpebral fissures, convergent strabismus, epicanthus, wide nasal bridge, small nose, low-set protruding ears with malformed helices, macrostomia, micrognathia, short philtrum, and short neck). ( B ) Real-time PCR analysis of CNTN6; upper panel, the duplication of CNTN6 in grandmother K (I-1); middle panel, the duplication of CNTN6 in father K (II-2) and proband K (III-1); and lower panel, the two copies of CNTN6 in patient’s K aunt (II-3) and her daughter (III-2). ( C ) The pedigree plot for family K; the dark, solid square represents the affected patient K, and the gray, solid square and circle represent father K and grandmother K, respectively.

Figure 4

Array CGH and real-time PCR analyses of family K. ( A ) The CNTN6 duplication in patient K, father K and grandmother K. ( B ) The CNTN6 duplication in father K. ( C ) The CNTN6 duplication in grandmother K. ( D ) Left to right: two copies of CHL1 and two copies of CNTN4 in patient F, father F and grandmother F.

Figure 5

A map of microdeletions and microduplications involving only CNTN6 that have been published in DECIPHER and in the literature, as well as those that were discovered in our patients. The microdeletions are shown in red, and the microduplications are colored blue.