Zebrafish homologs of 16p11.2, a genomic region associated with brain disorders, are active during brain development, and include two deletion dosage sensor genes

Deletion or duplication of one copy of the human 16p11.2 interval is tightly associated with impaired brain function, including autism spectrum disorders (ASDs), intellectual disability disorder (IDD) and other phenotypes, indicating the importance of gene dosage in this copy number variant region (CNV). The core of this CNV includes 25 genes; however, the number of genes that contribute to these phenotypes is not known. Furthermore, genes whose functional levels change with deletion or duplication (termed 'dosage sensors'), which can associate the CNV with pathologies, have not been identified in this region. Using the zebrafish as a tool, a set of 16p11.2 homologs was identified, primarily on chromosomes 3 and 12. Use of 11 phenotypic assays, spanning the first 5 days of development, demonstrated that this set of genes is highly active, such that 21 out of the 22 homologs tested showed loss-of-function phenotypes. Most genes in this region were required for nervous system development - impacting brain morphology, eye development, axonal density or organization, and motor response. In general, human genes were able to substitute for the fish homolog, demonstrating orthology and suggesting conserved molecular pathways. In a screen for 16p11.2 genes whose function is sensitive to hemizygosity, the aldolase a (aldoaa) and kinesin family member 22 (kif22) genes were identified as giving clear phenotypes when RNA levels were reduced by ~50%, suggesting that these genes are deletion dosage sensors. This study leads to two major findings. The first is that the 16p11.2 region comprises a highly active set of genes, which could present a large genetic target and might explain why multiple brain function, and other, phenotypes are associated with this interval. The second major finding is that there are (at least) two genes with deletion dosage sensor properties among the 16p11.2 set, and these could link this CNV to brain disorders such as ASD and IDD.Simons Foundation (Grant Number 95091

DISC1 genetics, biology and psychiatric illness

Psychiatric disorders are highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points towards DISC1 being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain

Structurele chromosoomherschikkingen in autisme spectrum stoornissen

Autisme spectrum stoornis (ASS) is een heterogene groep van aandoeningen met deficits in sociale interactie, communicatie en taalontwikkeling, en kenmerken van stereotiep en repetitief gedrag. Hoewel ASS een sterk genetische basis heeft, zijn bij de meerderheid van de patiënten de genetische oorzaken en overervingsmodellen nog niet opgehelderd. Slechts 10-15% van de patiënten hebben een enkelvoudig genetische oorzaak, zoals een puntmutatie of chromosomale herschikking, vb. een gebalanceerde translocatie. Vaak zijn deze monogene oorzaken gekoppeld aan een syndromale vorm van ASS. Recent onderzoek heft aangetoond dat zeldzame kopij nummer varianten geassocieerd zijn aan ASS. Deze factoren kunnen beschouwd worden als belangrijke risicofactoren met matig tot groot effect. De meeste chromosomale herschikkingen en mutaties zijn echter niet recurrent, wat snelle vooruitgang in het onderzoek naar autisme genetica bemoeilijkt. Chromosomale herschikkingen vormen echter een ideaal uitgangspunt voor de ontdekking van nieuwe genen in ASS. In dit doctoraatsonderzoek werden de breekpunten van complexe de novo schijnbaar gebalanceerde herschikkingen gekarakteriseerd bij 4 ASS patiënten. Aldus werden verscheidene positionele kandidaatgenen geïdentificeerd aan de breekpunten. Bijkomend werden ook cryptische breekpunt-geassocieerde deleties gevonden bij 2 patiënten. Voor 2 synaptische genen, CDH11 and CNTN3, werd bijkomende genetische en biologische evidentie gevonden voor hun betrokkenheid bij ASS. Daarom werden ze werden geselecteerd voor mutatieanalyse en/of associatiestudies. Voor CDH11 werd bijkomende genetische evidentie gevonden voor de betrokkenheid in ASS. Daarnaast identificeerden we ook een nieuw kandidaatgen, FAM120C, door studie van een complexe submicroscopische X-gebonden deletie. Verder onderzoek op dit gen is momenteel bezig. Ook voor DISC1, een gen geassocieerd aan schizophrenie, werd bijkomende genetische evidentie gevonden voor de betrookkenheid in ASS. Tenslotte leidde onderzoek van een familiale 118kb microdeletie in de recurrente 16p11.2 CNV regio, tot een verkleining van de kritische ASS regio van 27 naar 5 genen: SEZ6L2, MVP, CDIPT, ASPHD1 and KCTD13. Met behulp van familie- en associatiestudies, hebben we getracht de verschillende genetische varianten onder te brengen in een frequentie-effect spectrum. Ook worden de moeilijkheden die optreden bij genetische adviesverlening besproken, met name het ontrafelen van het precieze overervingsmechanisme. Aangezien de meeste varianten uniek zijn voor 1 patiënt of familie, blijft het een zeer grote uitdaging om hun effectgrootte te voorspellen.In de laatste jaren is duidelijk geworden dat CNV s belangrijke risicofactoren zijn in ASS. Hoewel deze bevindingen zeer nuttig kunnen zijn bij het stellen van een diagnose, is de tijd nog niet rijp voor de implementatie van deze CNVs in a priori risicopredictie.Dankwoord I List of abbreviations VII Table of Contents XI 1 Introduction 1 1.1 Autism and autism spectrum disorders 1 1.1.1 Definition and diagnostic classification 1 1.1.2 Prevalence 1 1.1.3 Phenotypic heterogeneity 2 1.2 The genetics of autism spectrum disorders 2 1.2.1 ASDs have a strong genetic basis 2 1.2.2 The genetics of ASD is complex 3 1.2.3 Genetic architecture in ASD 8 1.2.4 Neurobiological pathways in ASD 14 1.2.5 References 16 2 Objectives 23 3 Positional cloning in 4 patients with de novo apparently balanced rearrangements 25 3.1 Introduction 25 3.2 Patients and methods 25 3.3 Results 27 3.4 Supplementary information 31 3.5 References 32 4 Unique rearrangements 35 4.1 Cryptic CDH11 deletion in a non-syndromic ASD patient with a complex chromosomal rearrangement 35 4.1.1 Abstract 35 4.1.2 Introduction 35 4.1.3 Methods and patients 36 4.1.4 Results 42 4.1.5 Discussion 46 4.1.6 Supplementary information 49 4.1.7 References 51 4.2 Xp11.22 complex deletion in a patient with syndromic ASD 55 4.2.1 Abstract 55 4.2.2 Introduction 55 4.2.3 Patients and methods 56 4.2.4 Results 59 4.2.5 Discussion 65 4.2.6 Supplementary material 67 4.2.7 References 68 5 Rare inherited CNVs: DISC1 duplication in 2 brothers with autism and mild mental retardation 71 5.1 Abstract 71 5.2 Introduction 71 5.3 Patients and methods 72 5.4 Results 74 5.5 Discussion 77 5.6 Supplementary information 79 5.7 References 81 6 Recurrent CNV loci: narrowing the critical region for ASD on 16p11.2 85 6.1 Abstract 86 6.2 Introduction 86 6.3 Methods and patients 87 6.4 Results 90 6.5 Discussion 95 6.6 References 97 7 Frequent CNPs: a common 3p12.3 deletion in ASD 101 7.1 Abstract 101 7.2 Introduction 102 7.3 Methods and patients 103 7.4 Results 108 7.5 Discussion 114 7.6 Supplementary information 116 7.7 References 116 8 General discussion 119 8.1 Identification of novel ASD candidate genes 119 8.2 Confirmatory studies of selected novel ASD candidate genes 120 8.2.1 CDH11 121 8.2.2 CNTN3 122 8.2.3 FAM120C 122 8.3 Studies on previously implicated candidate genes and regions 123 8.4 Classification of genetic variants according frequency and effect size 124 8.5 The genetic overlap of ASD and schizophrenia 126 8.6 The challenges of genetic counseling in ASD 128 8.7 References 131 9 Scientific summary of the research 137 10 Nederlandstalige populaire samenvatting 139 11 Curriculum Vitae An Crepel 141nrpages: 172status: publishe

Mutation in POLA1 in a family with X-linked syndromic mental retardation

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DISC1 duplication in two brothers with autism and mild mental retardation

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.status: publishe

A complex Xp11.22 deletion in a patient with syndromic autism: Exploration of FAM120C as a positional candidate gene for autism

We present a male patient with sporadic Aarskog syndrome, cleft palate, mild intellectual disability, and autism spectrum disorder (ASD). A submicroscopic discontiguous deletion was detected on chromosome Xp11.2 encompassing FGD1, FAM120C, and PHF8. That the deletion encompassed FGD1 (exons 2-8) explains the Aarskog features while the deletion of PHF8 most likely explains the cleft palate and mild intellectual disability. We identify FAM120C as a novel X-linked candidate gene for autism for two reasons: first, a larger deletion encompassing FAM120C segregates with autism in a previously reported family and second, there is recent evidence that FAM120C interacts with CYFIP1, part of the FMRP (Fragile X Mental Retardation Protein) network. In the current study, resequencing of FAM120C in 87 Belgian male patients with autism spectrum disorder identified no novel mutations. Expression of Fam120c in mouse tissues showed enriched expression in pituitary, cerebellum, cortex, and pancreatic islets of Langerhans. Additionally, we found a cortical expression pattern of Fam120c similar to that of Fmr1. In conclusion, FAM120C is a novel candidate gene for autism spectrum disorder based on genetic evidence and the brain expression pattern. Thereby we highlight a role for FMRP network genes in ASD. © 2014 Wiley Periodicals, Inc.status: publishe