Draft for NIH Diagnostic Conference
The Role of Genetics in the Diagnosis of Autistic Disorder
Edwin H. Cook, Jr., M.D. Bennett L. Leventhal, M.D. David H. Ledbetter, Ph.D. -University of Chicago
Evidence for Genetic Factors in Etiology of Autistic Disorder Autistic disorder is a strongly genetic disorder (reviewed in 7). The concordance rate for a narrow diagnosis of autism is greater than 50% in monozygotic twins compared to 0% in dizygotic twins. For a broader phenotype including severe social and language impairment, concordance is greater than 90% in monozygotic twins compared to approximately 10% in dizygotic twins (2). The recurrence risk for autistic disorder in siblings has been estimated between 4.5% and 8.9%, but more data is necessary to refine and generalize this estimate from two studies from one research group (20,15). The relative recurrence risk (ls) for autistic disorder is conservatively 4.5%/0.1% = 45.
In addition, relatives without autistic disorder are also at increased risk for other disorders including a lesser variant of autistic disorder (12,19) and mood, anxiety, and substance abuse disorders (18,1,22,4).
The findings above have stimulated several predominantly affected sibling pair genome-wide screens to identify susceptibility genes for autistic disorder, including the first report with suggestive linkage between autistic disorder on 7q, 16p and 4p (14). Candidate gene studies have suggested linkage between the serotonin transporter gene (HTT) and autistic disorder (8) and between the GABAA receptor beta 3 subunit gene (GABRB3) (9). When specific mutations are identified, they may contribute to diagnosis of autism and particularly may be helpful in defining subgroups of patients with autistic disorder by identifying susceptibility genes underlying clinical or genetic heterogeneity seen in autistic disorder. However, statistical modeling of the nature of autistic disorder susceptibility genes in autistic disorder suggests that several loci act together to increase susceptibility to autistic disorder.
Currently Identifiable Genetic Disorders Associated with Autistic Disorder Several genetic disorders have been found in autistic disorder. Fragile X (FRAXA) syndrome has been shown to be associated with autistic disorder in several studies . However, several more recent studies using reliable diagnostic procedures have not found FRAXA in relatively large samples (9,21,25).
It is likely that FRAXA syndrome may be found predominantly in mentally retarded patients with PDD-NOS or other pervasive developmental disorders, but until more research is done, it is reasonable to expect research studies and genetic testing in patients with autistic disorder and mental retardation to include molecular screening for a diagnosis of FRAXA syndrome.
Tuberous sclerosis complex has also been found in several studies to be associated with autistic disorder (23,13). Although two genes for TSC have been identified, the presence of multiple mutations has delayed development of molecular diagnosis. Screening for TSC should be performed in all patients with autistic disorder by history designed to elicit symptoms of infantile spasms and by examination with a Wood's lamp to elicit hypopigmentation and other neurocutaneous stigmata. Several patients have been identified with myotonic dystrophy and Asperger's disorder (3). Myotonic dystrophy should be suspected in patients with a family history of weakness and with patients with motor impairment or facial weakness. DNA-based diagnosis of myotonic dystrophy is feasible and reduces the need for invasive electromyography (EMG) to establish diagnosis.
Several chromosomal disorders have been found in patients with autistic disorder and perhaps at an even higher frequency in patients with pervasive developmental disorders other than autistic disorder. Since a range of chromosomal disorders have been reported infrequently, cytogenetic analysis may identify several of the possibilities.
Of the chromosomal disorders found in association with autistic disorder and other pervasive developmental disorders, the most common chromosomal disorders in recent samples are abnormalities of the proximal long arm of chromosome 15 (15q11-q13), occurring in 1-4 % of consecutive cases meeting inclusion criteria for autistic disorder. The most common 15q11-q13 abnormalities identified are maternally inherited duplications, either pseudodicentric 15 (inverted duplication 15) or other atypical marker chromosomes with one or two extra copies of the area roughly corresponding to the typical Angelman syndrome (AS)/Prader Willi syndrome (PWS) deletion region of approximately 4 million base pairs. These patients typically have moderate to profound mental retardation.
In samples of patients with autistic disorder and I.Q. greater than 35, interstitial duplications of 15q11-13 have been found in over 1% of patients and at a greater frequency than FRAXA or other currently identifiable chromosomal disorders (9,21,25). Angelman syndrome (AS), due to an absence of maternally inherited 15q11-q13 material has been found in patients with autism and profound mental retardation (24,21). Autistic disorder or other pervasive developmental disorders have been found in patients with Prader-Willi syndrome (10), although at a decreased rate relative to the frequency of autistic disorder and other pervasive developmental disorders in Angelman syndrome or duplications of 15q11-13. Confirmation by FISH probes for the PWS/AS region is necessary to confirm cytogenetic evidence of 15q11-13 abnormalities.
ROLE OF GENETIC TESTING IN CURRENT DIAGNOSIS OF DISORDERS ASSOCIATED WITH AUTISTIC DISORDER AND OTHER OTHER PERVASIVE DEVELOPEMENTAL DISORDERS
Diagnostic assessment of children or adults with autistic disorder and other pervasive developmental disorders should include informing the parents what is and is not known about the genetics of autistic disorder. Since there are no data yet available for other pervasive developmental disorders, estimates for autistic disorder may be provided with the caveat that they may underestimate the recurrence risk for other pervasive developmental disorders. Currently, many centers do not routinely do chromosomal analysis as part of the diagnostic process, frequently due to the financial cost and absence of current therapeutic implications of diagnosing chromosomal disorders.
Identification of chromosomal disorders have two current purposes. The first is identification of specific etiology which may reduce the costs associated with other, sometimes more invasive, tests. This is particularly important for children with dysmorphology including cardiac, facial, ocular, or limb anomalies, diagnosis of pervasive developmental disorder not otherwise specified (25), diagnosis of family history of developmental disorders including autistic disorder and other pervasive developmental disorders. The second is establishing accurate recurrence risk for the parents and other family members that may lead to prevention through identification of disorders which increase the risk of autistic disorder recurrence risk to 50% instead of less than 10%. In addition to the increased risk to siblings, more distant relatives may be at risk, such as maternal aunts in FRAXA syndrome and inherited 15q11-q13 duplications (5). If the parents are not interested in genetic testing, such as chromosomal analysis, they should be counseled to inform their relatives of the possibility for recurrence in extended relatives.
Further Development of Genetics in the Diagnostic Process of Autistic Disorder Current cytogenetic banding methods are limited in resolution for the detection of genetic imbalances, and generally only detect deletions or duplications of 2-3 Mb in size. FISH analysis greatly increases the resolution, routinely allowing detection of deletions or duplications of cosmid sized genomic clones (30-40 kb). However, most FISH applications require a targeted testing approach to rule out imbalance of a specific genomic region, e.g., the proximal 15q deletion associated with Prader-Willi/Angelman syndromes.
Recent evidence suggests that human telomeric regions may be preferentially involved in subtle imbalances, and could account for up to 5-10% of all unexplained mental retardation with normal karyotype (11). The development of a complete set of FISH probes for human telomeres (17) now makes it possible to test this hypothesis by systematic analysis of telomere integrity on sporadic or inherited MR, including autism. For specific recurring imbalances, such as maternal duplication 15q, FISH analysis can be performed on interphase nuclei to further increase the resolution and efficiency of testing. Since this whole region of proximal 15q has been cloned and mapped at high resolution (6), a panel of FISH probes could be developed throughout this region for high resolution detection of duplication events throughout this region.
Identification of susceptibility mutations in autistic disorder may lead to either molecular diagnosis of subgroups with implications for prognosis or predictive of response to treatment. For example, since the short form of the serotonin transporter may lead to decreased brain expression of the serotonin transporter (16) and subsequent lower optimal mean dose of potent serotonin transporter inhibitors. It is already feasible to screen for most cytochrome p 450 mutations associated with much higher or lower metabolism of many medications used in autistic disorder and other pervasive developmental disorders through molecular methods. Finally, it must be emphasized that genetic does not mean pre-determined. It is unknown how many cases of phenylketonuria (PKU) with autistic disorder are currently prevented by mandatory neonatal screening for genetic mutations leading to PKU, by functional analysis of phenylalanine hydroxylase. Although the presence of heterogeneity and multiplicative inheritance makes the unequivocal identification of susceptibility genes in autistic disorder more difficult, multiplicative inheritance increases the chance that one of the genes to be identified may have more immediate implications for prevention or treatment than if a single gene was associated with development of autistic disorder.
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