Deletions of VCX-A and NLGN4: a variable phenotype including normal intellect.
Even when VCX-A and NLGN4 are deleted, normal intellect is possible—so test, don’t guess.
01Research in Context
What this study did
Doctors looked at two grown brothers who carry the exact same gene deletion. The missing piece wipes out VCX-A and NLGN4 on the X chromosome. Both men gave blood samples and took IQ tests. The team also checked each man for autism traits.
What they found
One brother scored in the normal IQ range. The other landed in the mild intellectual disability range. Neither brother met the cut-off for an autism diagnosis. Same gene change, very different minds.
How this fits with other research
NMStagnone et al. (2025) widens the lesson. They tracked 30 rare gene changes and saw the same spread: every variant raised autism risk, yet symptom shapes stayed unpredictable. The 2007 case is now one star in a sky of messy gene-to-behavior maps.
Emerson et al. (2023) adds a twist that looks like a clash. Their big review says girls with both ASD and ID show harsher social and repetitive problems than boys with the same labels. Our 2007 men had no ASD at all, and only one had ID. The gap is real but explainable: the review pools hundreds of mixed-gene cases, while the 2007 paper zooms in on one specific deletion that may simply dodge ASD more often.
Ajmone et al. (2022) echo the main point. In CdLS, normal IQ can hide inside the same mutation that causes severe delays in a cousin. Once again, the gene read-out is a poor crystal ball.
Why it matters
When a genetic report lands on your desk, treat it as a yellow sticky note, not a verdict. Plan full IQ, adaptive, and autism assessments no matter what the DNA says. Use the data to pick goals, not to limit them. If families ask, "Will my child talk or live on their own?" you can honestly answer, "The gene gives us clues, but we have to watch and teach to find out."
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02At a glance
03Original abstract
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.
Journal of intellectual disability research : JIDR, 2007 · doi:10.1111/j.1365-2788.2006.00880.x