LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions

LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone-3-lysine-9-associated chromatin around the LRFN5 gene itself (p < 0.01), possibly related to the male-restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20%–26% lower than expected from Hardy–Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild-type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism.publishedVersio

Mosaicism for combined tetrasomy of chromosomes 8 and 18 in a dysmorphic child: A result of failed tetraploidy correction?

<p>Abstract</p> <p>Background</p> <p>Mosaic whole-chromosome tetrasomy has not previously been described as a cause of fetal malformations.</p> <p>Case presentation</p> <p>In a markedly dysmorphic child with heart malformations and developmental delay, CGH analysis of newborn blood DNA suggested a 50% dose increase of chromosomes 8 and 18, despite a normal standard karyotype investigation. Subsequent FISH analysis revealed leukocytes with four chromosomes 8 and four chromosomes 18. The child's phenotype had resemblance to both mosaic trisomy 8 and mosaic trisomy 18. The double tetrasomy was caused by mitotic malsegregation of all four chromatids of both chromosome pairs. A possible origin of such an error is incomplete correction of a tetraploid state resulting from failed cytokinesis or mitotic slippage during early embryonic development.</p> <p>Conclusion</p> <p>This unique case suggests that embryonic cells may have a mechanism for tetraploidy correction that involves mitotic pairing of homologous chromosomes.</p

Characterisation of genomic imbalances in patients with mental retardation

A major cause of mental retardation is chromosomal abnormalities, but due to low sensitivity of conventional chromosomal karyotyping, these abnormalities may stay undetected, and the etiology of the impairment remains unknown. With the development of molecular cytogenetic methods, such as chromosome- and microarray-based comparative genomic hybridisation (HR-CGH and array-CGH), genome-wide detection of submicroscopic chromosomal abnormalities has become possible. To examine if implementation of such molecular cytogenetic methods would result in improved diagnostics of patients with mental retardation, we applied HR-CGH and array- CGH on patients with mental retardation to investigate the diagnostic utility of the two methods. In addition, the phenotype-genotype correlations in the patients were examined. By HR-CGH analysis, we found that cryptic genomic imbalances could be detected in five out of 50 examined patients with mental retardation (10%), despite normal findings on conventional karyotyping. Four of the findings were de novo and interstitial. Based on a larger population of 554 patients, the HR-CGH detection rate of cryptic imbalances was 7,2%. Of note, 90% of the findings were de novo, and only 25% of the findings involved a subtelomeric rearrangement. Subsequent analysis of HR-CGH positive samples by 1 Mb array-CGH demonstrated, as expected, a highly improved mapping accuracy of the array-CGH method compared to the HR-CGH method. Application of 1 Mb array-CGH analysis on 20 selected patients with normal findings on both G-banded karyotyping and HR-CGH analysis gave an additional detection rate of 20%, suggesting a high diagnostic yield of the 1 Mb array-CGH method. Three out of the four findings were de novo and interstitial. The capacity for detecting chromosomal mosaicisms by the CGH methods (both HR-CGH and array-CGH) was demonstrated by the unique finding of a mosaic combined tetraploidy for chromosomes 8 and 18 in a newborn with developmental delay, despite normal findings on G-banded karyotyping. The combination of several cytogenetic methods also made it possible to suggest candidate genes that might explain phenotypic features in two different families with mentally retarded individuals. In one family, a ~2,1 Mb sized deletion was located 1,6 Mb distal to a 14q21.1q23.2 paracentric inversion. The deletion involved 16 genes. Among these, SPTB causing spherocytosis, and PLEKHG3, a guanide nucleotide exchange factor for Rho GTPases, and a candidate gene for causing the phenotype of mild mental retardation. In another family, an 8,9 Mb subterminal 19p13 duplication was detected in a 2 ½-year-old proband with severe mental retardation and extreme precocious puberty. Global gene expression analysis did not reveal candidate gene(s) for the hormonal disturbance. The proband´s mother was shown to have a between-arm insertion of the duplicated 19p13 segment into 19q. The same balanced insertion was found in several other family members, including a maternally uncle who was also severely mentally retarded. Unexpectedly, a 3,9 Mb 2q23.3q24.1-deletion was detected in him. The deletion contained seven annotated genes, and of these, FMNL2, a suggested regulator of Rho-GTPases, and NR4A2, an essential gene for differentiation of dopaminergic neurons, are possible candidate genes for causing the phenotype of severe mental retardation. In summary, we have demonstrated the usefulness of HR-CGH and array-CGH as diagnostic tools for patients with mental retardation and have provided detailed genotype-phenotype information on 89 patients. The work also adds knowledge for further understanding of minor or cryptic chromosome imbalances that cause varying degrees of mental impairment, malformations and/or dysmorphism

LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions

LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone-3-lysine-9-associated chromatin around the LRFN5 gene itself (p < 0.01), possibly related to the male-restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20%–26% lower than expected from Hardy–Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild-type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism

A de novo 1.5 Mb microdeletion on chromosome 14q23.2-23.3 in a patient with autism and spherocytosis

Autism is a neuro-developmental disorder characterized by deficits in social interaction and communication as well as restricted interests or repetitive behaviors. Cytogenetic studies have implicated large chromosomal aberrations in the etiology of approximately 5–7% of autism patients, and the recent advent of array-based techniques allows the exploration of submicroscopic copy number variations (CNVs). We genotyped a 14-year-old boy with autism, spherocytosis and other physical dysmorphia, his parents, and two non-autistic siblings with the Illumina Human 1M Beadchip as part of a study of the molecular genetics of autism and determined copy number variants using the PennCNV algorithm. We identified and validated a de novo 1.5Mb microdeletion of 14q23.2-23.3 in our autistic patient. This region contains 15 genes including spectrin beta ( SPTB ), encoding a cytoskeletal protein previously associated with spherocytosis, methylenetetrahydrofolate dehydrogenase 1 ( MTHFD1 ), a folate metabolizing enzyme previously associated with bipoloar disorder and schizophrenia, pleckstrin homology domain-containing family G member 3 ( PLEKHG3 ), a guanide nucleotide exchange enriched in the brain, and churchill domain containing protein 1 ( CHURC1 ), homologs of which regulate neuronal development in model organisms. While a similar deletion has previously been reported in a family with spherocytosis, severe learning disabilities, and mild mental retardation, this is the first implication of chr14q23.2-23.3 in the etiology of autism and points to MTHFD1, PLEKHG3 , and CHURC1 as potential candidate genes contributing to autism risk

DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder

Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been whole-genome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4 × 10(-5) and 4 × 10(-6), respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 3'UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity

The Complement Control-Related Genes CSMD1 and CSMD2 Associate to Schizophrenia

Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia.Analysis of genetic association was based on data mining of genotypes from a German genome-wide association study and a multiplex GoldenGate tag single nucleotide polymorphism (SNP)-based assay of Norwegian and Danish case-control samples (Scandinavian Collaboration on Psychiatric Etiology), including 1133 patients with schizophrenia and 2444 healthy control subjects.Allelic associations were found across all three samples for eight common SNPs in the complement control-related gene CSMD2 (CUB and Sushi Multiple Domains 2) on chromosome 1p35.1-34.3, of which rs911213 reached a statistical significance comparable to that of a genome wide threshold (p value = 4.0 × 10(-8); odd ratio = .73, 95% confidence interval = .65-.82). The second most significant gene was CSMD1 on chromosome 8p23.2, a homologue to CSMD2. In addition, we observed replicated associations in the complement surface receptor CD46 as well as the major histocompatibility complex genes HLA-DMB and HLA-DOA.These data demonstrate a significant role of complement control-related genes in the etiology of schizophrenia and support disease mechanisms that involve the activity of immunity-related pathways in the brain