Review J Med Genet: first published as 10.1136/jmg.2008.060871 on 26 August 2008. Downloaded from Autistic phenotypes and genetic testing: state-of-the- art for the clinical geneticist C Lintas, A M Persico Laboratory of Molecular ABSTRACT towards a strong genetic component in ASD.3 Psychiatry & Neurogenetics, Autism spectrum disorders represent a group of Linkage and association studies have identified University Campus Bio-Medico, Rome, Italy and Department of developmental disorders with strong genetic underpin- numerous susceptibility genes, located on various Experimental Neurosciences, nings. Several cytogenetic abnormalities or de novo chromosomes, especially 2q, 7q, 15q and the X IRCCS. ‘‘Fondazione Santa mutations able to cause autism have recently been chromosome.89 The clinical heterogeneity of ASD Lucia’’, Rome, Italy uncovered. In this study, the literature was reviewed to probably reflects the complexity of its genetic highlight genotype–phenotype correlations between cau- underpinnings, involving multiple contributing Correspondence to: Dr A M. Persico, Laboratory of sal gene mutations or cytogenetic abnormalities and loci, genetic heterogeneity, epistasis and gene– Molecular Psychiatry and behavioural or morphological phenotypes. Based on this environment interactions.9 Interestingly, epidemio- Neurogenetics, University information, a set of practical guidelines is proposed to logical studies reported an incidence of 2–5 in ‘‘Campus Bio-Medico’’, Via Alvaro del Portillo 21, I-00128 help clinical geneticists pursue targeted genetic testing 10 000 newborn babies before 1985, whereas Rome, Italy; a.persico@ for patients with autism whose clinical phenotype is studies performed after the year 2000 converge unicampus.it suggestive of a specific genetic or genomic aetiology. upon rates of ASD as high as 20–60 in 10 000.12 13 This increase may stem from the use of broader Received 6 June 2008 diagnostic criteria and increased attention by the Revised 4 July 2008 12 13 Accepted 8 July 2008 Autism spectrum disorders (ASDs) represent a medical community, but a real increase in heterogeneous group of neurodevelopmental dis- incidence of ASD due to environmental and orders characterised by social and communication epigenetic factors acting upon a genetically vulner- deficits, accompanied by repetititive and stereo- able background is also likely.9 typed behaviours, with onset before 3 years of Genetic screens represent a powerful tool when age.12From a diagnostic standpoint, ASDs coincide dealing with monogenic mendelian disorders, with the Diagnostic and statistical manual of mental characterised by direct genotype–phenotype corre- disorders, 4th edition (DSM-IV) criteria for perva- lations. In the case of complex disorders, such as sive developmental disorders, including autistic ASD, widespread genetic testing would not only be disorder, Asperger syndrome, childhood disintegra- expensive and time-consuming, but also generally tive disorder, Rett syndrome and ‘‘pervasive devel- inappropriate due to the aetiological complexity opmental disorder not otherwise specified’’ (PDD- described above.9 Nonetheless, there are at least http://jmg.bmj.com/ NOS).12 However, the concept of ASD is some- two instances where genetic testing can be what complementary to DSM-IV categorical diag- successfully used in complex disorder: to evaluate noses, because it underlines that autistic-like traits the degree of genetic susceptibility to a certain and behaviours represent a continual spectrum disease and to identify rare monogenic or cytoge- rather than clinically defined diagnostic categories.3 netic forms of the disease. The appropriate use of The male:female sex ratio for autistic disorder is genetic testing in these two instances is good 4:1, implying an involvement of the X chromo- clinical practice for the following reasons: (1) the on September 30, 2021 by guest. Protected copyright. some and/or imprinting mechanisms. Autism is identification of susceptibility variants can allow associated with seizures and mental retardation the implementation of prevention programmes, as (MR) in up to 30% and 80% of cases, respec- exemplified by familial breast and ovarian cancers tively.45 A prenatal origin of the disease is involving BRCA1 and BRCA2 mutations,14 or supported by neuroanatomical and neuroimaging familial colon cancer;15 (2) the identification of studies, showing abnormalities stemming from the exact genetic cause of an otherwise un- disturbed neurodevelopmental processes physio- explained disease, especially when it affects chil- logically occurring during the first and second dren, can significantly reduce the levels of guilt and trimester of pregnancy.67 anxiety in parents and improve their compliance Genetics strongly contributes to the pathogen- with medical interventions and to rehabilitation esis underlying ASDs.89 Rett syndrome, a mono- programmes. genic disorder affecting female carriers of During the past few years, genetic research in mutations in the MeCP2 gene,10 has been described ASDs has begun achieving some important suc- in detail previously.11 In this review, we focus on cesses, including the identification of several the remaining ASDs and especially on autistic vulnerability loci and of a few cytogenetic disorder, the neuropsychiatric disorder with the abnormalities or single-base mutations able to highest monozygotic twin concordance rate (73– cause autism (see below). In order to transfer this 95%), the highest heritability (.90%, as estimated recently acquired knowledge into clinical practice, by twin studies) and a noticeable sibling recurrence it is critical to define a set of phenotypic inclusion This paper is freely available 89 online under the BMJ Journals risk (5–6% for non-syndromic autism). In addi- criteria that must be met by affected probands to unlocked scheme, see http:// tion the presence of mild autistic traits in first- justify their enrolment in a specific genetic testing jmg.bmj.com/info/unlocked.dtl degree relatives of patients with autism points programme. Accordingly, these genetic screening J Med Genet 2009;46:1–8. doi:10.1136/jmg.2008.060871 1 Review J Med Genet: first published as 10.1136/jmg.2008.060871 on 26 August 2008. Downloaded from programmes must be designed to use clearly targeted, feasible to be at increased risk of MR and some were apparently and cost-effective strategies. We reviewed the relevant literature diagnosed with Asperger syndrome, suggesting that CNVs may to look for specific correlations between ASD-causing gene also be associated with milder forms of autism, perhaps not mutations or cytogenetic abnormalities and clinical ASD accompanied by dysmorphic features. Marshall et al20 assessed phenotypes (mainly behavioural and/or morphological ASD 427 unrelated patients with ASD and 500 controls, finding 27 phenotypes). We hope this information will be useful to guide (6.3%) cases carrying de novo CNVs, which may be especially clinical geneticists in establishing and implementing effective present in simplex (4/56 = 7.1%) rather than in multiplex (1/ genetic screening programmes for those patients with ASD 49 = 2.0%) families. Many, but not all patients, display whose phenotype is suggestive of a specific genetic or genomic dysmorphic features and/or neurological impairment. aetiology. Christian et al21 reported the presence of 7 de novo and 44 inherited CNVs in 397 patients with ASD. The clinical features were not discussed in detail, but no evidence of signs or SYNDROMIC AUTISM symptoms shared by patients carrying de novo chromosomal Syndromic autism (ASD associated with a known cause) microdeletions or microduplications was reported. Using array- represents approximately 10% of all ASD cases and is often 816 based technologies, others have reported novel and possibly associated with malformations and/or dysmorphic features. recurrent microdeletion syndromes, affecting regions such as Unlike ‘‘idiopathic’’ or ‘‘primary’’ ASD, syndromic autism 22–24 17 16p11.2 and 2p15–16.1. These studies have confirmed that shows an equal male:female sex ratio. Syndromic autism can CNVs can be associated with a variety of clinical features, be associated with well-known genetic or genomic disorders including non-ASD behavioural disorders in siblings of patients (including fragile X syndrome, neurofibromatosis, tuberous with autism. Therefore, the presence of malformations, sclerosis, untreated phenylketonuria, and Angelman, Cornelia dysmorphic features and/or severe neurological symptoms de Lange and Down syndromes), with de novo chromosomal strongly points toward a possible cytogenetic origin for ASDs, rearrangements detectable by karyotyping (duplication of the but their absence does not exclude it. The progressive transfer of maternal 15q11-13 region, deletions of chromosome 2q37, 7q31, array-based approaches from the laboratory into clinical practice 22q11 and microdeletions of chromosome 22q11.2) and with will enhance our ability to detect an increasing number of rare environmental events (prenatal central nervous system submicroscopic de novo chromosomal abnormalities. infection by rubella or cytomegalovirus, prenatal exposure to valproic acid or thalidomide).816 The recent advent of array-based high-resolution genomic GENES INVOLVED IN MONOGENIC FORMS OF AUTISM analysis has dramatically increased the power to detect small de Neuroligin 3/4 genes (NLGN3, NLGN4) novo genomic deletions and duplications, down to a few Neuroligins are cell-adhesion molecules localised postsynatpti-