Association of folate metabolism gene polymorphisms with autism susceptibility and symptom severity in the Chinese...

Folate metabolism gene polymorphisms may play an important role in the pathogenesis of autism spectrum disorder (ASD). However, most studies have primarily used single candidate gene typing strategies (such as targeted polymerase chain reaction technology), and current findings remain inconsistent.

To investigate the association of folate metabolism gene polymorphisms with ASD susceptibility and symptom severity among Chinese children.

Whole-exome sequencing (WES) was conducted to systematically screen for coding region variants of key genes in the folate metabolism pathway among children with ASD, focusing on identifying polymorphisms with high mutation frequencies and potential pathogenic effects. A case-control study was then conducted to explore the association of candidate folate metabolism gene polymorphisms with the susceptibility and severity of ASD.

WES was performed on 70 children with ASD, and the case-control study included 170 children with ASD and 170 healthy controls. WES revealed that 84.3% (59/70) of children with ASD carried potentially pathogenic variants enriched in folate metabolism pathways. MTHFR C677T and MTRR A66G were significantly associated with an increased risk of ASD in both codominant and dominant models (P < 0.05). The dominant model of MTRR A66G was also significantly associated with higher scores in the domains of social relations, body and object use, social and adaptive skills, total scores on the Autism Behavior Checklist, as well as emotional reactivity, nonverbal communication, and activity level on the Childhood Autism Rating Scale (P < 0.05).

Most children with ASD carry deleterious variants in folate metabolism-related pathways. MTHFR C677T and MTRR A66G mutations are significantly associated with ASD.