Familial 18q12.2 deletion supports the role of RNA-bindingprotein CELF4 in autism spectrum disorders

Deletion of 18q12.2 is an increasingly recognized condition with a distinct neuropsychiatricphenotype. Twenty-two patients have been described with overlapping neurobehavioraldisturbances including developmental delay, intellectual disability of variable degree, seizures,motor coordination disorder, behavioral/emotional disturbances, and autism spectrumdisorders. The CUGBP Elav-like family member 4 (CELF4) gene at 18q12.2 encodes a RNAbindingprotein that links to RNA subsets involved in pre- and postsynaptic neurotransmissionincluding almost 30% of potential autism-related genes. Haploinsufficiency of CELF4 wasassociated with an autism or autistic behavior diagnosis in two adult patients with de novo18q12.2 deletions. We report on a girl and her mildly affected mother with a 275 kb deletion at18q12.2 involving CELF4 and KIAA1328 whose disruption is not associated with any knowndisease. The child was diagnosed with syndromic intellectual disability and autism at 6 years ofage. Her mother had minor dysmorphisms, mild intellectual disability, and autistic behavior. Thedeleted region reported in this family is one of the smallest so far reported at 18q12.2. This isalso the first full clinical description of maternally inherited CELF4 haploinsufficiency. Thepresent study refines the molecular and neuropsychiatric phenotype associated with 18q12.2deletion leading to CELF4 haploinsufficiency and provides evidence for a role for CELF4 in braindevelopment and autism spectrum disorders.