Deletions of VCX-A and NLGN4: a variable phenotype including normal intellect.
BACKGROUND
Patients with Xp22.3 interstitial and terminal deletions have been shown to be affected by intellectual disability (ID) or autism. Previously, VCX-A (variably charged protein X-A), located at Xp22.3, was introduced as a gene for ID and its presence was suggested to be sufficient to maintain normal mental development. Recent reports suggest that mutations in NLGN4 (neuroligin 4), located at that same region, are involved in autistic disorders and ID.


METHODS
In the current case study, we clinically and molecularly describe a pedigree of three generations affected by contiguous gene syndrome that includes features of X-linked ichthyosis and Kallmann syndrome.


RESULTS
Molecular analysis revealed the presence of an interstitial deletion spanning approximately 4.5Mb at Xp22.3. The centromeric breakpoint was localized between markers DXS1467 and DXS8051, proximal to KAL-1. The telomeric breakpoint was localized between markers DXS89 and DXS1060, distal to NLGN4. The deletion of VCX-A and NLGN4 in this family prompted us to examine the cognitive functions of our two adult patients using comprehensive intellectual and neurocognitive assessment. Normal intellectual function was found in one patient and mild ID was revealed in the other. Neither patient met any Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition criteria for a pervasive developmental disorder such as autism.


CONCLUSIONS
These findings suggest that deletion of VCX-A and NLGN4 can result in variable phenotypic features and that normal mental development can be achieved despite this deletion, emphasizing the importance of environmental factors and possible modifier genes.
Macarov
M
M
Department of Human Genetics, Hebrew University-Hadassah Medical School and Hadassah University Hospital, Jerusalem, Israel.
Zeigler
M
M
Newman
J P
JP
Strich
D
D
Sury
V
V
Tennenbaum
A
A
Meiner
V
V
D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal; D041321:Chromosomes, Human, X / Q000235:genetics; D003072:Cognition Disorders / Q000175:diagnosis / Q000453:epidemiology; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D005819:Genetic Markers; D006801:Humans; D008607:Intellectual Disability / Q000453:epidemiology / Q000235:genetics*; D007360:Intelligence; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D011795:Surveys and Questionnaires
D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D005819:Genetic Markers; D008565:Membrane Proteins; C430845:NLGN4X protein, human; D009687:Nuclear Proteins; C404411:VCX protein, human