only 20 patients with deletions of 18q12.2 have been reported in the literature . in 15 of these patients , the deletions were examined with chromosome analysis , and in the remaining 5 patients molecular investigations identified deletions ranging from 3.2 to 24  mb in size . common clinical findings included intellectual disability , behavioral disorders , seizures , eye manifestations , obesity , and mild or absent dysmorphic facial features . in recent years , the use of high - resolution cytogenetic techniques has led to the identification of numerous microdeletion syndromes , where patients with overlapping deletions share clinical features . however , the shared deletions often exceed hundreds of kb or even several mb , encompassing many genes that hamper the identification of the exact gene(s ) underlying the associated phenotype . in contrast , truncation of single genes  for example , by small intragenic deletions or by chromosomal translocation or inversion breakpoints  can directly identify a disease - causing gene . here we describe a patient with a prenatally detected de novo translocation involving chromosomes 12 and 18 , with febrile seizures in childhood , borderline intelligence , developmental and behavioral disorders , myopia , and obesity . we characterized the rearrangement with snp array and next - generation sequencing ( ngs ) and found truncation of celf4 , which has previously been suggested as a neurodevelopmental candidate gene . this report illustrates the utility of high - resolution genome - wide techniques in identifying neurodevelopmental genes . the patient was identified though a nation - wide study of prenatally detected de novo balanced structural rearrangements . the study was approved by the danish scientific ethics committee and written informed consent was obtained . amniocentesis was performed due to advanced maternal age , and a de novo reciprocal translocation involving chromosomes 12 and 18 was diagnosed . the child was born by uncomplicated vaginal delivery at 40 weeks of gestation with a birth weight of 4000  g and birth length 55  cm . according to the mother , he walked independently at 12 months and there was no delay in language development . at 23 months of age owing to minor neurological deficits and difficulties with complex motor tasks , he was diagnosed with minimal brain dysfunction at age 4 . at the age of 6 , he was described as aggressive , with immature and oppositional behavior , having problems with impulsivity and attention shifting , and with a lack of emotional reciprocity . at the age of 13 , he was tested with weschler intelligence scale for children - revised and found to have an iq of 71 , and he was diagnosed with behavioral disorder , oppositional defiant disorder , and mixed specific developmental disorder ( all according to icd-10 ) . a physical examination at the age of 25 years revealed no dysmorphic features . his height was 180  cm , weight 110  kg , and head circumference 61  cm . he was obese with a body mass index of 34 ; according to the mother , obesity has been present since the age of 67 years as a result of uninhibited eating behavior . at the age of 27 years , he was screened for major psychiatric disease using the mini international diagnostic interview version 5.0.0 that refers to the dsm - iv . no single diagnosis could be pinpointed . signs of low iq and autistic behavior with indications of concrete thinking , impairment of social interaction skills , vagueness in description of others , lack of concentration over time , hyperactivity , and impulsive behavior were seen during the interview . there was significant impairment in occupational and social areas , and a general incapacity for labor market affiliation was manifest . in his youth , he was intensely preoccupied with trains and unable to develop peer relationships . genomic dna was extracted by conventional methods from peripheral blood , and whole - genome copy number variation ( cnv ) analysis was performed with the affymetrix genome - wide human snp array 6.0 ( affymetrix , santa clara , ca , usa ) . raw intensity data files were analyzed with the genotyping console software ( affymetrix ) according to the manufacturer 's recommendations . mate pair libraries were prepared using the mate pair library v2 kit ( illumina , san diego , ca , usa ) . two- to three - kilobase pair fragments were isolated , end - repaired using a mix of natural and biotinylated dntps , blunt - end ligated using circularization ligase , and fragmented to 200400  bp . biotinylated fragments were isolated and end - repaired and a - overhangs were added to the 3-ends . paired - end adapters were ligated to the fragments and the library was amplified by 18 cycles of pcr . mate pair libraries were subjected to 2  36 bases paired - end sequencing on a genome analyzer iix ( illumina ) , following the manufacturer 's protocol . reads were aligned to a reference genome using bowtie allowing up to two mismatches in the seed region . reads not aligning uniquely were discarded from further analysis . paired reads aligning to different chromosomes or with unexpected strand orientation were extracted to identify potential translocation and inversion breakpoints , respectively . breakpoints were only considered as candidates if they were confirmed by at least six independent paired reads with end - reads mapping within a 6-kb region . predicted breakpoints were filtered against known in - house variants based on data from 30 individuals with known breakpoints . the translocation breakpoint was confirmed by pcr amplification and sanger sequencing of the breakpoint - spanning fragments . amniocentesis was performed due to advanced maternal age , and a de novo reciprocal translocation involving chromosomes 12 and 18 was diagnosed . the child was born by uncomplicated vaginal delivery at 40 weeks of gestation with a birth weight of 4000  g and birth length 55  cm . according to the mother , he walked independently at 12 months and there was no delay in language development . at 23 months of age owing to minor neurological deficits and difficulties with complex motor tasks , he was diagnosed with minimal brain dysfunction at age 4 . at the age of 6 , he was described as aggressive , with immature and oppositional behavior , having problems with impulsivity and attention shifting , and with a lack of emotional reciprocity . at the age of 13 , he was tested with weschler intelligence scale for children - revised and found to have an iq of 71 , and he was diagnosed with behavioral disorder , oppositional defiant disorder , and mixed specific developmental disorder ( all according to icd-10 ) . a physical examination at the age of 25 years revealed no dysmorphic features . his height was 180  cm , weight 110  kg , and head circumference 61  cm . he was obese with a body mass index of 34 ; according to the mother , obesity has been present since the age of 67 years as a result of uninhibited eating behavior . at the age of 27 years , he was screened for major psychiatric disease using the mini international diagnostic interview version 5.0.0 that refers to the dsm - iv . signs of low iq and autistic behavior with indications of concrete thinking , impairment of social interaction skills , vagueness in description of others , lack of concentration over time , hyperactivity , and impulsive behavior were seen during the interview . there was significant impairment in occupational and social areas , and a general incapacity for labor market affiliation was manifest . in his youth , he was intensely preoccupied with trains and unable to develop peer relationships . genomic dna was extracted by conventional methods from peripheral blood , and whole - genome copy number variation ( cnv ) analysis was performed with the affymetrix genome - wide human snp array 6.0 ( affymetrix , santa clara , ca , usa ) . raw intensity data files were analyzed with the genotyping console software ( affymetrix ) according to the manufacturer 's recommendations . mate pair libraries were prepared using the mate pair library v2 kit ( illumina , san diego , ca , usa ) . two- to three - kilobase pair fragments were isolated , end - repaired using a mix of natural and biotinylated dntps , blunt - end ligated using circularization ligase , and fragmented to 200400  bp . biotinylated fragments were isolated and end - repaired and a - overhangs were added to the 3-ends . paired - end adapters were ligated to the fragments and the library was amplified by 18 cycles of pcr . mate pair libraries were subjected to 2  36 bases paired - end sequencing on a genome analyzer iix ( illumina ) , following the manufacturer 's protocol . reads were aligned to a reference genome using bowtie allowing up to two mismatches in the seed region . reads not aligning uniquely were discarded from further analysis . paired reads aligning to different chromosomes or with unexpected strand orientation were extracted to identify potential translocation and inversion breakpoints , respectively . breakpoints were only considered as candidates if they were confirmed by at least six independent paired reads with end - reads mapping within a 6-kb region . predicted breakpoints were filtered against known in - house variants based on data from 30 individuals with known breakpoints . the translocation breakpoint was confirmed by pcr amplification and sanger sequencing of the breakpoint - spanning fragments . a total of 28  986  673 paired reads passed the chastity filter ; 13  689  000 paired reads were aligned uniquely and 204  319 were chimeric pairs ( end - reads mapping to different chromosomes ) . we removed non - clustering chimeric pairs leaving a total of 49 chimeric clusters genome - wide that were visually filtered against known variants . the breakpoint at chromosome 12 affected no annotated genes whereas the breakpoint at chromosome 18 truncated celf4 . the translocation breakpoint at chromosome 18 was confirmed by pcr amplification and subsequent sanger sequencing of the breakpoint - spanning fragments that revealed a small sequence of micro homology ( agga ) , likely to facilitate the translocation ( supplementary figure 1 ) . additionally , ngs revealed an associated inversion at chromosome 18 with breakpoints at 18q12.2 and 18q22.1 that truncated celf4 and loc643542 . re - evaluation of the karyotype confirmed the cryptic complex rearrangement , and cnv analysis revealed small de novo deletions ( < 150  kb in size ) corresponding to all four mapped breakpoints ( supplementary table s1 ) . here , we report a male patient with a translocation involving chromosomes 12q and 18q with borderline iq , developmental and behavioral disorders , myopia , obesity , and a history of febrile seizures in childhood . using snp array and ngs , we identified a cryptic complex rearrangement that truncated 2 refseq genes : the protein coding gene celf4 ( also known as brunol4 ) at 18q12.2 and the non - coding rna loc643542 at 18q22.1 . few of the previously reported patients with deletions of 18q12.2 were characterized sufficiently both clinically and molecularly to allow direct phenotype  genotype comparisons . however , as illustrated in table 1 there is a considerable phenotypic overlap with our patient . gilling et al reported a patient with childhood autism , severe myopia , and a de novo translocation , t(5;18)(q34;q12 ) . mcentagart et al described a patient with a de novo del(18)(q11.2q12.2 ) and a phenotype remarkably like the one reported here consisting of mild intellectual disability ( iq 61 ) , developmental delay , febrile seizures , clumsiness , behavioral difficulties including poor concentration and hyperactivity , distractibility and learning difficulties , and no facial dysmorphism . this patient was only examined with conventional karyotyping but the reported phenotype included intellectual disability , a history of fine motor problems , and seizures in childhood . her behavior was described as impulsive , aggressive , defiant , restless , and labile autistic - like . although celf4 was previously found disrupted in patients with overlapping phenotypes , no phenotype has been associated with the non - coding rna loc643542 , thus we find it highly likely that haploinsufficiency of celf4 causes the described phenotype . celf4 is expressed in various tissues with high expression in both fetal and adult human brain . in frog embryos ( xenopus laevis ) , celf4 is solely expressed in the nervous system , including the optic veiscles , suggesting an important role in both brain and eye development . furthermore , celf4 is highly expressed in mouse brain and celf4 insufficient transgenic mice develop convulsive seizures , hyperactivity , and late - onset body weight gain . not only is celf4 conserved from drosphila to mouse and human , but the genomic landscape next to celf4 is also evolutionary conserved harboring ultra - conserved elements ( uce ) , and it has been suggested that uces may be directly involved in neurodevelopmental disorders . we found celf4 to be disrupted in a patient with borderline iq , developmental and behavioral disorders , myopia , obesity , and a history of febrile seizures in childhood . the phenotype resembles that of patients with 18q12.2 deletions illustrating that celf4 haploinsufficiency has a key role in explaining their phenotype . this report , and the finding of celf4-deficient mice with overlapping traits , for example , seizures , hyperactivity , and obesity , adds to the growing evidence that celf4 is important for the brain development and in the disposition to obesity .
only 20 patients with deletions of 18q12.2 have been reported in the literature and the associated phenotype includes borderline intellectual disability , behavioral problems , seizures , obesity , and eye manifestations . here , we report a male patient with a de novo translocation involving chromosomes 12 and 18 , with borderline iq , developmental and behavioral disorders , myopia , obesity , and febrile seizures in childhood . 
 we characterized the rearrangement with affymetrix snp 6.0 array analysis and next - generation mate pair sequencing and found truncation of celf4 at 18q12.2 . 
 this second report of a patient with a neurodevelopmental phenotype and a translocation involving celf4 supports that celf4 is responsible for the phenotype associated with deletion of 18q12.2 . 
 our study illustrates the utility of high - resolution genome - wide techniques in identifying neurodevelopmental and neurobehavioral genes , and it adds to the growing evidence , including a transgenic mouse model , that celf4 is important for human brain development .