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Background  Copy number variations (CNVs) can contribute to variable degrees of fitness and/or disease predisposition. Recent studies show that at least 1% of any given genome is copy number variable when compared to the human reference sequence assembly. Homozygous deletions (or CNV nulls) that are found in the normal population are of particular interest because they may serve to define non-essential genes in human biology.    Results  In a genomic screen investigating CNV in Autism Spectrum Disorders (ASDs) we detected a heterozygous deletion on chromosome 10p12.1, spanning the Patched-domain containing 3 ( PTCHD3 ) gene, at a frequency of ~1.4% (6/427). This finding seemed interesting, given recent discoveries on the role of another Patched-domain containing gene ( PTCHD1 ) in ASD. Screening of another 177 ASD probands yielded two additional heterozygous deletions bringing the frequency to 1.3% (8/604). The deletion was found at a frequency of ~0.73% (27/3,695) in combined control population from North America and Northern Europe predominately of European ancestry. Screening of the human genome diversity panel (HGDP-CEPH) covering worldwide populations yielded deletions in 7/1,043 unrelated individuals and those detected were confined to individuals of European/Mediterranean/Middle Eastern ancestry. Breakpoint mapping yielded an identical 102,624 bp deletion in all cases and controls tested, suggesting a common ancestral event. Interestingly, this CNV occurs at a break of synteny between humans and mouse. Considering all data, however, no significant association of these rare  PTCHD3  deletions with ASD was observed. Notwithstanding, our RNA expression studies detected  PTCHD3  in several tissues, and a novel shorter isoform for  PTCHD3  was characterized. Expression in transfected COS-7 cells showed  PTCHD3  isoforms colocalize with calnexin in the endoplasmic reticulum. The presence of a patched (Ptc) domain suggested a role for  PTCHD3  in various biological processes mediated through the Hedgehog (Hh) signaling pathway. However, further investigation yielded one individual harboring a homozygous deletion ( PTCHD3  null) without ASD or any other overt abnormal phenotype. Exon sequencing of  PTCHD3  in other individuals with deletions revealed compound point mutations also resulting in a null state.    Conclusion  Our data suggests that  PTCHD3  may be a non-essential gene in some humans and characterization of this novel CNV at 10p12.1 will facilitate population and disease studies.

Human PTCHD3 nulls: rare copy number and sequence variants suggest a non-essential gene