Molecular cytogenetic analysis of a familial interstitial deletion Xp22.2‐22.3 with a highly variable phenotype in female carriers

Abstract

We describe a familial interstitial deletion of 7.7-Mb involving Xp22.2-22.3. The deletion was transmitted from an asymptomatic mother to her two children with severe developmental delay, no speech development and autistic behavior. Assessment of the deletion boundaries by FISH and PCR analyses indicated that the deletions encompasses 27 genes. Several of these genes are associated with known disorders, like KAL1 (Kallmann syndrome), steroid sulfatase (STS) (X-linked ichtyosis), and arylsulfatase E (ARSE) (chondrodysplasia punctata). The deletion also includes all four VCX genes (VCX-A, VCX-B1, VCX-B, and VCX-C) and the neuroligin 4 (NLGN4) gene. VCX-A deficiency has been shown previously to be associated with mental retardation and NLGN4 mutations lead to mental retardation in conjunction with autism. Functional deficiency of both MRX genes, VCX-A and NLGN4, are most likely associated with the impaired cognitive development of the patients described here. The phenotype associated with the Xp deletion was highly variable in female carriers and might be attributed to unfavorable X inactivation. However, all the 27 genes included in the deleted interval escape X inactivation and are expressed at variable levels from the normal X chromosome. Thus, the overall X inactivation pattern and inter-individual expression variability of the genes in distal Xp might be determinants of the phenotype associated with the deletion.

Neuroligin 2 Controls the Maturation of GABAergic Synapses and Information Processing in the Retina

“…These alterations functionally translate into impaired visual processing and retinal output, and suggest that deletion or mutation in NLs may induce important alterations already at sensory synapses and not only in higher brain areas. Of note, mutations in NLs are linked to cases of autism and mental retardation (Jamain et al, 2003;Laumonnier et al, 2004;Chocholska et al, 2006;Lawson-Yuen et al, 2008;Yan et al, 2008), and NL deletion-mutant mice have been introduced as genetic models of autism (Tabuchi et al, 2007;Jamain et al, 2008). In particular, visual alterations have been described in some cases of autism (Cook, 1990;Bertone et al, 2005;Dakin and Frith, 2005), and it will be interesting to explore the impact of other NL isoforms on the organization and function of the retinal network.…”

Characterization of the solution structure of a neuroligin/β-neurexin complex

“…Since the first study showing a linkage in a twin sets between the incidence of the ASD and mutations in the NLGN3 and 4 genes, several structural variants (including point mutations, truncations, and exon deletions) of the coding regions of neurexin (NX) and neuroligin (NL) were found to be associated with ASD and mental retardation (1)(2)(3)(4)(5)(6)(7). Emerging evidence also indicates that rare variations in copy number and common variations within the genes encoding NX-1 and NX-3 contribute to ASD susceptibility (8,9).…”

Cell Adhesion Molecules and Their Involvement in Autism Spectrum Disorder

“…In this study, an R451C mutation within the esterase domain of neuroligin 3 was identified in a Swedish family with two affected boys [25] . Various other mu- tations in NLGN3 and NLGN4X genes have been identified in ASD patients [26][27][28][29][30][31][32] . Some of these mutations were studied at the functional level to reveal their possible linkage with ASD.…”