Molecular Screening Reveals De Novo Loss-of-Function NR4A2 Variants in Saudi Children with Autism Spectrum Disorders:...

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Nuclear receptor superfamily 4 group A member 2 (NR4A2) dysregulation is linked to autistic spectrum disorder (ASD), speech impairment, and neurodevelopmental delay (NDD).
• The precise role of NR4A2 in ASD pathogenesis remains unclear.
• Understanding genetic factors contributing to ASD is crucial for early diagnosis and intervention.

Purpose of the Study:

• To investigate the role of NR4A2 variants in the genetic basis of ASD among Saudi children.
• To analyze the frequency and impact of NR4A2 variants across different age ranges and ASD severities.

Main Methods:

• Exome sequencing (ES) of 338 children with ASD from 315 unrelated families.
• Genomic DNA extracted from peripheral blood mononuclear cells (PBMCs).
• Trio genetic analyses for probands with identified NR4A2 variants.

Main Results:

• Identified 10 de novo NR4A2 variants (5 indels/nonsense, 2 missense, 3 splicing) in 8 unrelated probands (2.37%) and 2 affected siblings.
• Three NR4A2 variants were recurrent in both affected and unaffected carriers.
• Pathogenic/loss-of-function (LoF) variants were identified, alongside variants of uncertain significance (VUS).

Conclusions:

• A significant frequency of NR4A2 variants, including recurrent ones, was found in the Saudi ASD cohort.
• These findings suggest a notable contribution of NR4A2 variants to ASD etiopathogenesis in this population.
• Further research is warranted to elucidate the functional impact of these variants.