Scan statistic-based analysis of exome sequencing data identifies FAN1 at 15q13.3 as a susceptibility gene for schizophrenia and autism

Abstract

We used a family-based cluster detection approach designed to localize significant rare disease-risk variants clusters within a region of interest to systematically search for schizophrenia (SCZ) susceptibility genes within 49 genomic loci previously implicated by de novo copy number variants. Using two independent wholeexome sequencing family datasets and a follow-up autism spectrum disorder (ASD) case/control whole-exome sequencing dataset, we identified variants in one gene, Fanconi-associated nuclease 1 (FAN1), as being associated with both SCZ and ASD. FAN1 is located in a region on chromosome 15q13.3 implicated by a recurrent copy number variant, which predisposes to an array of psychiatric and neurodevelopmental phenotypes. In both SCZ and ASD datasets, rare nonsynonymous risk variants cluster significantly in affected individuals within a 20-kb window that spans several key functional domains of the gene. Our finding suggests that FAN1 is a key driver in the 15q13.3 locus for the associated psychiatric and neurodevelopmental phenotypes. FAN1 encodes a DNA repair enzyme, thus implicating abnormalities in DNA repair in the susceptibility to SCZ or ASD.

Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature

“…A recent study showed significant enrichment of multiple rare, nonsynonymous variants spanning a 20-kb region overlapping FAN1 in schizophrenia and ASD as compared with controls, thus implicating this gene, which encodes a DNA repair nuclease, as another potential contributor to the 15q13.3-deletion neuropsychiatric phenotype. 33 Other BP4-BP5 region genes with brain expression include TRPM1, encoding a calcium permeable cation channel. TRPM1 is a leading candidate for the visual impairment in children with homozygous 15q13.3 deletions, given its involvement in heterogeneous autosomal recessive forms of complete congenital stationary night blindness (CSNB1C, OMIM 613216).…”

Crystal structure of a Fanconi anemia-associated nuclease homolog bound to 5′ flap DNA: basis of interstrand cross-link repair by FAN1

“…Depletion of FAN1 in zebrafish resulted in activation of a DNA damage response, apoptosis, and kidney cysts (Zhou et al 2012). Furthermore, the FAN1 locus has been linked to schizophrenia and autism (Ionita-Laza et al 2014).…”

Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease

“…In addition to KIN (24), mutations in FAN1 have been associated with predisposition to colorectal and pancreatic cancer as well as autism and schizophrenia (28)(29)(30)(31), raising the possibility that defects in ICL repair may be associated with a wide variety of diseases. In vitro studies showed that human FAN1 can degrade ICL-containing oligonucleotides past the lesion in replication-like intermediates, thereby unhooking the ICLs (32)(33)(34).…”