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Exploring Autism: the Search for a Genetic Etiology

Katharine E. Yoder

Penn State College of Medicine




Autistic Disorder is described in the DSM IV as having the characteristics of:

  1. Qualitative impairment in social interaction,
  2. Qualitative impairments in communication,
  3. Restricted repetitive and stereotyped patterns of behavior, interests, and activities,

And delays or abnormal functioning in at least one of the following areas, with onset prior to age 3 years:

  1. Social interaction
  2. Language used in social communication, or
  3. Symbolic or imaginative play,

And the disturbance is not described by Rett’s Disorder or Childhood Disintegrative Disorder.


Incidence à possibility of a genetic link

  • General population: 0.04% to 0.1%, Males 3-4x > Females
  • Twin studies: Monozygotic (MZ) and Dizygotic (DZ)

–     Autism in concordance rates occurs MZ 300x> DZ

–     Autism penetrance not 100% (36.3-95.7%) in MZs

–     Strong arguments for genetic as well as non-genetic influences

  • Family studies

–     Risk of autism in sibling of autistic child 3% (general pop 0.1%)

–     Cognitive disabilities in parents and siblings of autistic inconclusive

–     Bias in studies due to less # of siblings if one autistic child in family


Chromosomal Regions of Interest 

15q11-13 inverted duplication

  • Region associated with dyslexia and genes for 3-γ-aminobyturic acid (GABA)-A

receptor subunits

  • Prader-Willi/Angelman critical region (PWACR) – two types of duplications

–     proximal to PWACR, no clinical significance, familial, normal

–     within PWACR, often with DD and autism, familial or de novo

maternally-derived often > significance vs. paternally-derived

= imprinting?


The X chromosome

  • Fragile X: expansion of CGG repeat sequence of Xq27.3 (FMR1 gene)

–     2nd most common cause of mental retardation, associated with macro-

orchidism, long face with a large jaw, and large everted ears

–     autism in fragile X’ers 6.9-25%; fragile X in autistic 0-13.1%

–     behavior of autistic and fra X’ers only slightly overlap

  • Male autism > Female autism

–     penetrance differs between the sexes?

–     “susceptibility genes” on the X chromosome? Studies + and –

–     inheritable “susceptibility genes” only from maternal X chromosome?


Tuberous sclerosis (AD) with variable clinical picture of infantile spasms, “ash leaf”

hypopigmented lesions, sebaceous adenoma, and a shagreen patch

  • 20-61% with TS had autism, often also have seizure disorder
  • 0.4-2.9% with autism had TS
  • TS + autism, have tubers in temporal lobes


17p11.2 (Neurofibromatosis 1 gene); Neurofibromatosis I or von Recklinghausen’s

syndrome with clinical picture of café au lait spots, neurofibromas, freckling in axilla or

inguinal area, optic glioma, Lisch nodules, bone abnormality, and a first degree relative

with NF1

  • NF in autism 0.2-14%


Other candidate genes exist, but are novel finds and warrant further study:

  • 11p15.5 is the c-Harvey-ras oncogene (ras involved in cell growth, signaling, cell architecture and intracellular transport) – both the D4 receptor and tyrosine hydroxylase genes are located in this area
  • 2q EN2(mice) ≈ MP4 (human), expressed in cerebellum development
  • 16p13.3 case report of autism and Tourette’s
  • Dopamine D1, D2 and D5 receptors
  • genes within HLA complex
  • 7q
  • serotonin transporter gene (serotonin sometimes a treatment)



Several theories regarding genetics and autism can be explored:

  • One or multiple genes are responsible for autism

–     several genes with small effects multiply into the disorder

–     gene-gene interaction, presence of one abnormality is sufficient

–     gene locus specific with major effects (15q, X chromosome)

  • A combination of genetics and environment are responsible for autism

–     twin and family studies and genetic vs. non-genetic arguments


The truth is:

  • No one genetic link can be made to all cases of autism

–     yet

–     support for the spectrum of autistic disorders, some say

–     is autism a disorder within other diseases (high frequency of other

neurobiopsych diagnoses)


With regards to patient care:

  • How far do we go with diagnosis?

–     chromosome analysis (specifically for 15q); FRAXA DNA screen;

Wood’s Lamp exam (TS)

  • How important is it to pursue a genetic etiology?

–     Proper counseling

–     Disease prevention



The papers investigated in this evaluation are review papers and one clinical trial. Please consult specific references for methods.




American Psychiatric Association: Diagnostic and Statistical Manual or Mental Disorders, Fourth ed., Text Revision. Washington, DC, American Psychiatric Association, 2000.

Asherton PJ and Curran S. 2001. Approaches to gene mapping in complex disorders and their application in child psychiatry and psychology. British Journal of Psychiatry 179: 122-128.s

Bolton PF, Dennis NR, Browne CE, Thomas NS, Veltman MWM, Thompson RJ and Jacobs P. 2001. The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. American Journal of Medical Genetics (Neuropsychiatric Genetics) 105: 675-685.

Cook EH. 2001. Genetics of autism. Child and Adolescent Psychiatric Clinics of North America 10(2): 333-50.

Eigsti IM and Shapiro T. 2003. A systems neuroscience approach to autism: biological, cognitive, and clinical perspectives. Mental Retardation and Developmental Disabilities Research Reviews 9: 206-216.

Lauritsen MB and Ewald H. 2001. The genetics of autism. Acta Psychiatrica Scandinavica 103: 411-427.

Trottier G, Srivastava L and Walker CD. 1999. Etiology of infantile autism: a review of recent advances in genetic and neurobiological research. Journal of Psychiatry and Neuroscience 24(2): 103-115.

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