X Chromosome Variants Help Explain Sex Bias in Autism | Spectrum

Hot spots: Four sites on the X chromosome were 60% richer in rare and damaging variants in autistic boys than in their nonautistic brothers.

Tim Vernon, LTH NHS Trust / Scientific Source

Rare genetic variants that a boy inherits from his mother’s X chromosome may increase his risk of autism, Tourette’s syndrome or attention deficit/hyperactivity disorder (ADHD), a new study find.

“This breakthrough helps us understand the genetic mechanisms underlying male vulnerability to autism spectrum disorders, Tourette’s syndrome and ADHD,” says the study’s lead researcher. Jeremy Willseyassociate professor of psychiatry and behavioral sciences and co-director of the Psychiatric Cell Map Initiative at the University of California, San Francisco.

The work also implicates the X-chromosome gene MAGEC3 in autism for the first time. Analyzing the X chromosomes of more people with autism or other neurodevelopmental disorders could help “identify additional risk genes,” Willsey says. “Studying these genetic risk factors may shed light on the mechanisms underlying risk and resilience for these conditions, and thus putative treatments.”

Autism, Tourette’s syndrome and ADHD appear significantly more often in boys, even after accounting for potential diagnostic biases. One possible explanation is that boys, who usually have only one X chromosome, cannot compensate for an altered copy of an X chromosome gene in the same way that girls, who have two X chromosomes, can. .

Previous attempts to find genetic variants on the X chromosome that are associated with autism, Tourette’s syndrome and ADHD in idiopathic cases – in which there is no known genetic cause – have, however, proven unsuccessful. , perhaps in part because these efforts did not analyze enough people. to detect such variants.

OIllsey and his colleagues analyzed the exomes – the protein-coding regions of the genome – of 65 families that have one autistic son and at least two non-autistic sons, all born to non-autistic parents, and are part of the Simons Simplex Collection (SSC). (The SSC is funded by the Simons Foundation, Spectrumthe parent organization of .)

The non-autistic women in the study, they found, consistently passed on four X-chromosomal regions — which house 149 genes — to their autistic sons, but not to their non-autistic sons. This pattern of inheritance may reflect how DNA from a woman’s X chromosomes may mix or “recombine” when creating eggs.

The four sites were 60% richer in rare and damaging variants in the autistic sons than in their nonautistic brothers. And autistic boys had about twice as many rare and damaging variants affecting genes that rank among the top half expressed in the brain. Similar results emerged from a follow-up analysis of 11,391 autistic boys and their 1,549 unaffected brothers who participate in SPARKanother effort supported by the Simons Foundation.

When researchers analyzed exome data from 570 boys and men with Tourette syndrome and 332 boys and men with ADHD, they found effects even stronger than those seen in autistic people. People with Tourette syndrome were 2.1 times more likely to have rare and damaging variants on their X chromosomes than controls, while those with ADHD were 2.5 times more likely. The scientists detailed their findings online last month in a preprint article submitted to Nature Communication.

Further analysis of 13,052 additional autistic boys and men and 2,295 non-autistic controls from the combined SSC and SPARK datasets revealed the novel association between autism and MAGEC3. This gene belongs to the melanoma antigen (MAGE) family, which is associated with a wide range of conditions, including those related to neurodevelopment.

“They were able to identify an autism risk gene that had not been detected until now,” explains Aaron Besterman, assistant clinical professor of psychiatry at the University of California, San Diego, who was not involved in this study. “As more is uncovered, this may shed light on the mechanism of male genetic vulnerability to neurodevelopmental disorders, and specifically the potential for overlapping of these disorders, which typically occur together in patients, particularly males. men.”

Research on the apparently higher rates of neurodevelopmental disorders in boys often focuses on “feminine protective effect‘, says Besterman. This theory suggests that girls are inherently more resistant to factors that predispose someone to autism. “There has been a lot less focus on male genetic vulnerability, so it’s good to see new work on this topic,” he says.

Spontaneous or “de novo” mutations in non-sex chromosomes are linked to decrease in nonverbal IQ, show previous studies. The researchers, however, did not find a similar association with rare and damaging X-chromosome variants in autistic boys. Instead, autistic boys with above-average nonverbal IQs may have 40% more of these variants than controls.

Overall, about 20, 24, and 28 percent of rare and damaging X-chromosome variants may be linked to autism, ADHD, or Tourette syndrome, respectively, the team estimates. These variants, however, contributed to risk in only 2-3% of cases for the three conditions.

“This work in no way suggests that mothers in general are responsible for their children’s diagnoses,” Willsey says.

Cite this article: https://doi.org/10.53053/DGQN8318

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