Fine mapping of Xq11.1-q21.33 and mutation screening of RPS6KA6, ZNF711, ACSL4, DLG3, and IL1RAPL2 for autism spectrum disorders (ASD).
No clear autism mutations were found in five X-linked genes, yet the Xq21 region remains under suspicion.
01Research in Context
What this study did
Kantojärvi et al. (2011) zoomed in on a slice of the X chromosome called Xq11.1-q21.33. They picked five genes under that spot and read every letter of each gene in people with autism.
The goal was simple: find a harmful spelling change that could explain why autism runs in these families.
What they found
No clearly bad mutations turned up in any of the five genes. The team did see a weak linkage signal at Xq21.1, so the area still looks interesting.
In short, the genes they tested are probably not the main culprits, but the neighborhood remains on the suspect list.
How this fits with other research
Allen-Brady et al. (2010) used the same AGRE family set and found a linkage peak on the opposite arm of the X chromosome (Xp22). Both studies point to the X chromosome, just different blocks, so the clues are spreading across the whole chromosome rather than piling on one spot.
Casey et al. (2009) took a similar gene-by-gene approach and did find rare harmful variants in APBA2. Katri’s group came up empty this time, showing that candidate sequencing sometimes hits and sometimes misses.
YSánchez-Luquez et al. (2025) later reported a tiny deletion in another X gene, NXF5, in one patient with autism. Together these papers build a slow-growing list of rare X-linked changes, each explaining only a sliver of cases.
Why it matters
When you talk genetics with families, you can say the X chromosome keeps popping up in research, but single-gene answers are still scarce. Keep an eye on updated panels; today’s negative genes may be replaced by new candidates tomorrow.
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02At a glance
03Original abstract
About 80% of cases with autism express intellectual disability. Both in autism and in mental retardation without autism the majority of the cases are males, suggesting a X-chromosomal effect. In fact, some molecular evidence has been obtained for a common genetic background for autism spectrum disorders (ASD) and X-linked mental retardation (XLMR). In several genome-wide scans (GWS), evidence for linkage at X-chromosome has been reported including the GWS of Finnish ASD families with the highest multipoint lod score (MLS) of 2.75 obtained close to DXS7132 at Xq11.1. To further dissect the relationship between autism and genes implicated in XLMR, we have fine-mapped Xq11.1-q21.33 and analyzed five candidate genes in the region. We refined the region using 26 microsatellite markers and linkage analysis in 99 Finnish families with ASD. The most significant evidence for linkage was observed at DXS1225 on Xq21.1 with a nonparametric multipoint NPL(all) value of 3.43 (P = 0.0004). We sequenced the coding regions and splice sites of RPS6KA6 and ZNF711 residing at the peak region in 42 male patients from families contributing to the linkage. We also analyzed ACSL4 and DLG3, which have previously been known to cause XLMR and IL1RAPL2, a homologous gene for IL1RAPL1 that is mutated in autism and XLMR. A total of six novel and 11 known single nucleotide polymorphisms were identified. Further studies are warranted to analyze the candidate genes at Xq11.1-q21.33.
Autism research : official journal of the International Society for Autism Research, 2011 · doi:10.1002/aur.187