A Close Family Relationship DiSC1 XXX DV
Vaniria Setser
The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.
We describe the identification and delineation of an inherited 2.07 Mb microduplication in 1q42.2 in two brothers with autism and mild mental retardation. Since this duplication was not present in 1577 Belgian persons, we consider this as an extremely rare variant which has the potential to provide further insight into the genetics of autism. The duplication contains seven genes including the DISC1 gene, an interesting candidate gene that has been associated to schizophrenia, bipolar disorder, autism and Asperger syndrome. In this report we describe additional analyses undertaken to investigate the causal relationship of the duplication to the autism phenotype. We conclude that the 1q42.2 microduplication probably confers susceptibility to autism in the current family. This study is a typical illustration of the difficult interpretation of causality of a very rare variant in neuropsychiatric disease and the challenge of genetic counselling in a particular family.
Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.
Details of the translocation family are given in Thomson et al. [18] (see also: Supplementary methods: Diagnoses and phenotypic models in the family). This study was approved by the Multi-Centre Research Ethics Committee in Scotland (09/MRE00/81). All study participants gave their written, informed consent.
Validation of GATK VQSR modelling showed that 94% pass variants and 52% of failed variants were validated by custom designed Taqman assays (Supplementary methods: Variant validation-VQSR filter). All variants were therefore retained initially and an additional filter for Mendelian segregation in the family applied.
Variance component linkage analyses were performed using the SOLAR software package [23] (Supplementary methods: Linkage analysis). LOD scores were adjusted for deviation of the phenotype distribution from normal but, due to the nested nature of the phenotypes, were not adjusted for multiple testing. SNVs within the genomic regions under the linkage peaks were phased using the software SHAPEIT (v2.r83725) and the 1000 Genomes Phase 1 integrated reference panel26, incorporating the pedigree information to increase accuracy (Supplementary methods: Haplotype phasing). Minimal haplotype regions were defined by recombination breakpoints in the affected individuals in the family. Mixed logistic or linear regression models, fitting the inverse relationship matrix as a random effect to control for familial structure, were used to test phenotype associations of haplotypes using ASREML-R (www.vsni.co.uk/software/asreml). The significance of fixed effects within the model was assessed using a conditional Wald F-test. A model p-value of
Association studies of affective disorder and related traits were performed in two population-based cohorts: Generation Scotland: Scottish Family Health Study (GS:SFHS) [24,25,26] and UK Biobank (UKB) [27], fitting principal components and cohort/phenotypes appropriate covariates using subsets of unrelated individuals (see Supplementary methods: UK Population-based cohorts: GS:SFHS and UKB and region-wide association analyses).
The minimum haplotype regions were defined for each genome-wide significant peak and the diagnoses of the carriers identified (Supplementary Figure 3). Table 2 shows the boundaries of these linkage regions. Information on all the genes in the regions is given in Supplementary Table 3. The minimum haplotypes under the linkage peaks on chromosomes 1 and 11 (chr1q, chr11q1 and chr11q2), although adjacent to the translocation, do not include the breakpoints (hg19: chr1: 231,950,368 and chr11: 90,361,108; Supplementary Figure 3a and 3b). The maximum multipoint LOD scores in the region of the translocation are driven both by individuals with the translocation, who share a wide flanking region, and by individuals with psychiatric diagnoses who carry discrete regions shared with the translocation carriers (Supplementary Information: Haplotype phasing). The combination of haplotypes carried by each family member and their diagnosis are shown in Supplementary Table 4 (see also Fig. 2). The chr1q haplotype and the chr11q1 haplotypes are defined by all 19 of the translocation carriers and additional affected individuals who do not carry the translocation (Supplementary Figures 3a and 3b). The chr11q2 haplotype is not present in three of the translocation carriers; this region is defined by recombination events in two translocation carriers (ID 18 and 19), beyond the recombination event inherited from the married-in parent, and an individual with rMDD who does not carry the translocation. The chr5q haplotype is shared by 10 translocation carriers and 7 non-carriers (Supplementary Figure 3c).
Sequence-level analyses of the regions on chr1q and chr11q1, shared by the translocated chromosomes that have undergone recombination (IDs 18 and 19; Supplementary Figure 3b) and three non-translocation carriers (siblings with IDs 44 and 47, and the child of 44, ID 87; Fig. 2; Supplementary Table 4: Summary of haplotype segregation in the t(1;11) family), show that these haplotypes are near identical to those on the derived chromosomes. Although it is not possible to definitely show that these haplotypes are inherited from the familial parent, these regions span multiple haplotype blocks in the Scottish population and the combinations found on the derived chromosomes occur at
Although these cross-trait associations are in some cases within the same subregion, as defined by the recombination rates across the region in the 1000 Genome UK population, for example, for affective disorder, cognitive variable and number of episodes in CNTN5 (Supplementary Figure 7c), or affective disorder, MDD and Mill Hill vocabulary in PDE4D (Supplementary Figure 7d), this is not true for affective disorder and psychological distress in CNTN5 (Supplementary Figure 7c), or affective disorder and MDD in chr4q (Supplementary Figure 8d). These results suggest that variants in the genes within the family-defined haplotypes are associated, at low penetrance, in the UK population and may modulate aspects of phenotype such as number of episodes and cognitive ability.
The associations detected in the two UK-based cohorts are not significant at the genome-wide level. The nominal associations with affective disorder and related traits suggest that, despite the evidence for a strong individual effects in the family, these were not observed at a population level with the sample sizes tested.
The evidence for high heritability and familial clustering in psychiatric disorders is counter balanced by the limitations of current diagnostic criteria, over-lapping symptomatology and absence of definitive biomarkers, physiology or pathology. Using whole-genome sequencing, we investigated the existence of disease-modifying loci in a large Scottish pedigree in which a balanced t(1;11) translocation predisposes to major psychiatric disorders. The Scottish t(1;11) family is exceptional because of its size, longitudinal clinical follow-up and detailed molecular genetic study. The foundational finding is of a t(1;11) translocation that disrupts three genes: DISC1, DISC2 and DISC1FP, alters DISC1 expression and results in production of abnormal fusion transcripts [39, 40]. Direct disruption of DISC1 impacts on neurodevelopment, glutamate-signalling, cognitive ability and liability to psychiatric disorder [41,42,43,44,45,46,47,48,49,50]. Studies on individuals from the t(1;11) family have identified abnormalities in brain structure particularly white matter integrity [51] and cortical thickness [18, 52], and in brain activation identified through P300 amplitude and latency [53], as well as activation during working memory tasks, and altered glutamate signalling [18]. These functions are congruent with prevailing hypotheses of neurodevelopmental and synaptogenic origins of SCZ and related disorders. However, the penetrance of the t(1;11) is incomplete and the variability in both age of onset and presentation of symptoms remained unexplained.
PAT, WRM and DJP conceived the work, oversaw the analyses, and wrote the manuscript. NMR, JL and MK performed analyses and wrote the manuscript. SM, SWM, AA-S, GD, EG and CH performed analyses. IJD, DHRB, SML, AMM and KLE contributed scientific insight and edited the manuscript. B.D. provided data and contributed scientific insight. All authors commented on drafts of the paper.
WRM has participated in Illumina sponsored meetings over the past 4 years, and received travel reimbursement and an honorarium for presenting at these events. Illumina had no role in decisions relating to the study/work to be published, data collection and analysis of data and the decision to publish. WRM has participated in Pacific Biosciences sponsored meetings over the past 3 years and received travel reimbursement for presenting at these events. WRM is a founder and shareholder of Orion Genomics. WRM is a member of the scientific Advisory Board of RainDance, Inc.
Millar et al. (2000) isolated and sequenced a translocation breakpoint region on chromosome 1q42 that had been identified by St. Clair et al. (1990) in a large Scottish family with mental and/or behavioral disorders, including schizophrenia (see 604906), schizoaffective disorder, recurrent major depression, and adolescent conduct and emotional disorders. Within the 1q42 chromosomal region, Millar et al. (2000) identified 2 novel genes directly disrupted by the translocation, which the authors termed 'disrupted in schizophrenia' 1 and 2 (DISC1 and DISC2, 606271). The major DISC1 gene is predicted to encode an 854-amino acid protein containing a globular N-terminal domain and a helical C-terminal domain with the potential to form a coiled-coil by interaction with another protein(s). Northern blot analysis identified a 7.5-kb mRNA transcript with ubiquitous expression. DISC2 apparently specifies a single exon thought to be a noncoding RNA molecule that is antisense to DISC1, an arrangement that has been observed at other loci where the antisense RNA may regulate expression of the sense gene. Millar et al. (2000) suggested that DISC1 and DISC2 may confer susceptibility to psychiatric illnesses.
7fc3f7cf58