The Chromosomal Errors that Cause Autism Spectrum Disorders

Page content

Overview of Autism Spectrum Disorders Chromosomal Errors

Autism is defined as a neurodevelopmental disorder with three main diagnostic criteria: impairments in social interactions, communication, and an insistence on sameness. The disorder is classified under autism spectrum disorders (ASD), an umbrella term including other disorders such as Asperger’s syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), Rett syndrome, and childhood disintegrative disorder. ASD is one of the most heritable neurodevelopmental disorders, though the major path of inheritance is still not yet known. ASD, like most other disorders, is not a clear distinct diagnosis; each individual diagnosed on the spectrum varies from the next. The etiology of ASD had yet to be determined, however, based on previous twin studies, it is clear that a large genetic factor exists.

Using twins as subjects to identify potential genetic associations built the foundations of finding the cause of ASD. The first autism twin study (1977), compared 11 monozygotic twins and 10 dizygotic twins and provided valuable information, however the sample size was too small to report any considerable findings.

In the 1990s the study was replicated and the sample size doubled, finding a 60-80% concordance rate between monozygotic twins and a 0-5% rate between dizygotic twins. These studies have solidified the idea that there must be a genetic component; however, having a complete genetic factor would require concordance rates higher than 80%. There must be some other underlying factor.

A popular theory in the field of ASD and genetics is heterogeneity, meaning that defects in different loci, or genes, may cause the same phenotype. The large range of symptoms across individuals with ASD suggests that locus heterogeneity is a probable theory.

Linkage Studies

Studying the entire genome can help to identify large chromosomal regions in families within a given phenotype such as ASD. These studies suggest the involvement of 15 or more genes in ASD. A significant result of one study has reported linkage on chromosomes 2q and 3q while another reports of significance on chromosomes 7q, 13q, 16p, and 17q. Researchers have been analyzing these specific parts of the chromosomes, with the goal of finding a single cause.

A variety of other tests have analyzed associations between specific genes and ASD. While the tests are not conclusive the results demonstrate a possible link between specific genes and ASD.

Chromosome 15q11-q13 Region

The 15q11-q13 region has been a large focus of multiple associations in AS based on a maternally inherited 15q11-q13 duplication syndrome. Analyzing this syndrome can shed light on a possible underlying genetic mechanism in this region even with patients who do not have the duplication.

Results in this region have varied greatly. An initial study reviewed a significant association at 155CA-2, a polymorphism mutation within the gamma-amino butyric acid receptor (GABA). The study showed that patients with this mutation shared higher scores on the “insistence on sameness” triad, showing a higher prevalence in ritualistic behavior. The same study also claims that there is a large evidence for linkage at D15S511. Patients under this category tended to have savant skills, specializing in one or more areas of expertise or ability that are in contrast with the patient’s overall limitations. Researchers have continued investigating GABA receptors and have found a large association of mutation with subjects expressing ASD.

Serotonin transporter gene (SLC6A4)

The serotonin gene is a primary candidate gene based on patients with ASD having higher levels of serotonin than otherwise typical peers (known as hyperserotonemia). A variable number tandem repeat polymorphism has been found on the SLC6A4 promoter region which affects transcription of the gene, possibly causing the higher levels of serotonin. However, with contradictory results from different researchers, the studies have expanded to include other polymorphisms within or near the transporter gene, such as a closer look into the 5-HTTLPR repeat intron. Again, the majority of the studies conflict with one another.

Linkage studies also show some evidence in the region. A study reported that a linkage in 17q overlapping with the SLC6A4 gene tend to give elevated scores on a rigid/compulsive factor derived from the ADI-R (Autism Diagnostic Interview).

Enough evidence has been produced to suggest that SCL6A4 is involved with ASD; however more studies need to be completed. The few families that already have been examined do not represent the pattern observed in the overall population. Locus heterogeneity is believed to have some effect in the varying phenotypes (such as aggression or rigidity in behavior), but more research needs to be completed to verify the importance of SLC6A4 and ASD.

Reelin gene (RELN)

Protein abnormalities caused by RELN have been analyzed in post mortem brain studies of ASD. One such study has shown an expression of a “trinucleotide repeat polymorphism” in a region of RELN. However, three additional studies have found no evidence of association between RELN and the trinucleotide repeats. Investigations of particular candidate genes have been inconclusive; however, the RELN gene may still prove important in the etiology of ASD.

Neuroligin genes (NLGN3 and NLGN4)

Neuroligin genes, located on the X chromosome, encode proteins specializing in cell-adhesions needed for synapse formation. Several deletions that have been identified in patients on the spectrum occurred on Xp, where NLGN4 is located. The counterpart on the Y chromosome in males, NLGN4Y has expressed a similar pattern in male ASD patients.

Because of the findings on NLGN4, a NLGN3 mutation was found in a study of two brothers both placed on the spectrum. However, this study was never duplicated, so it is very difficult to make a connection between NLGN3 and ASD.

NLGN mutations express a variety of syndromes, from X-linked mental retardation to Asperger, autism, and PDD-NOS. Based on the results of a study of 10 carrier males, the patients did not share any morphological features that would cause a large diagnostic investigation. However, evaluating this gene in a larger population may clarify the role of neuroligin genes and ASD.

Multiple ankyrin repeat domains 3 gene (SHANK3)

SHANK3 is located on chromosome 22q13.3 and encodes a protein used in a complex of synapses where it binds directly to neuroligins. Two studies have shown a correlation between mutations affecting SHANK3 and an ASD phenotype, mainly characterized by severe verbal and social deficits.

Along with NLGN3 and NLGN4 mutations, SHANK3 mutations are extremely rare, affecting only around 1.1% of ASD patients. Yet, the correlations between the two studies suggest that patients on the spectrum with severe impairments of socialization and language may be good candidates for SHANK3 mutation screening. More studies on the SHANK3 gene have found that disruptions to it have strong associations as an ASD related risk gene. These observations recommend that regulation of SHANK3 gene might be crucial for the development of speech and socialization in humans.

Methyl-CpG-binding protein 2 gene (MECP2)

Methyl-CpG-binding protein 2 attaches to methylated chromosomal regions that contain a high quantity of CG nucleotide bases. The protein is a transcriptional repressor involved with inhibiting down-stream genes. Mutations in this gene located on the X chromosome occur in 75-80% of females with Rett syndromes, whereas mutations in males are generally lethal. The clinical phenotype depends upon the type of mutation and the specific x-inactivation pattern, which is highly skewed in the presence of mutations affecting x-linked genes, such as NLGN3 and MECP2, but is not significantly skewed in ASD families.

Overall, mutations in MECP2 are rare, around 1% of the general female ASD population. MECP2 is a gene with wide-ranging interactions and effects; it is important that researchers include complexity into existing models for understanding how MECP2 and other gene partners might be involved in the etiology of ASD.

Chromosomal Abnormalities

There have been many reports of chromosomal abnormalities and a possible causation of autism. Chromosomal abnormalities in association with ASD have been found on every single chromosome, including the sex chromosomes. Because of the high number of abnormalities, the results taken from the research support the theory of heterogeneity in chromosomal abnormalities for ASD.

Duplications of Chromosome 15q11-q13

Duplications of this region were demonstrated in a smaller study of autistic males. In addition to being on the spectrum, the males also expressed other disorders and physical abnormalities such as seizure disorder, development of a hunched back called kyphosis, and epicanthic folds, a skin fold in the upper eyelids.

Another study was completed with around 140 probands on the spectrum, in which around 1% had the duplication. It is important to note that it is only the maternally inherited duplication that leads to ASD. Deleting the single active copy of the gene results in a total loss of expression of the affected gene producing the disease phenotype. In familial cases, duplication of this region from the maternal chromosome gave an increased risk of ASD while from the paternal it had typically no effect.

Chromosome 7

Chromosome 7 has proved very important in the investigation of ASD. Translocations between chromosomes 7 and 13 have identified the 7q31 gene as RAY1. Inversions between chromosome 22 and 12 occur in the same region and could potentially disrupt the same gene. Mutations of the same RAY1 gene have been found in multiple patients with ASD. While chromosome 7 points to a causal onset of ASD the genetic factor model of ASD has not yet consistently explained ASD’s variable phenotype across the spectrum.

22q11 Deletion Syndrome

Several cases of ASD with this particular deletion have been grouped into certain syndromes, such as DiGeorge syndrome, Velocardio-facial syndrome, and the 22q11 deletion syndrome. An examination in a study of 32 children and young adults with this deletion found 56% had a neuropsychiatric disorder, 31% were on the spectrum, 44% had a previous diagnosis of attention deficit/hyperactivity (ADHD) disorder, and 16% had both ASD and ADHD. In another study 103 patients diagnosed with ASD were tested for the deletion and none were found. Because of the results, more evidence would be needed to prove the deletion as causal or coincidental.

Does ASD have a genetic component?

As stated previously, the etiology of ASD is currently unknown. There is no doubt that there is a feeling of disappointment in the field of autism genetics because concrete answers have not come more easily. Finding the single cause to a spectral disorder seems almost impossible, but by researching candidate genes, researchers are coming closer to finding a key genetic model to explain the inheritance of ASD. The overlap of genomic mutations give rise to the variability of the syndromes noted on the spectrum; however, not all patients with autism are the same. This may be due to such a broad diagnostic criteria listed in the DSM-IV (Diagnostic and Statistical Manual of Mental Disorder). I believe that due to ASD’s ability to vary so widely between patients, the criteria listed must be revised.

Recent advances in the genetics of autism emphasize its heterogeneity; therefore it is not surprising that ASD is a spectral disorder, having a wide variety of symptoms. However, we cannot expect to find the single “cause” for a disorder that covers such an extreme in symptoms and diagnoses.


  • Geschwind, D. (2009). Advances in Autism. The Annual Review of Medicine, 60, 367-380.
  • Lintas, C., & Persico, A. M. (2009). Autistic phenotypes and genetic testing; state-of-the-art for the clinical geneticist. Journal of Medical Genetics, 46, 1-8.
  • Loat, C. S., & Curran, S. (2008). Methyl-CpG-binding protein 2 polymorphisms and vulnerability to autism. Genes, brain, and behavior, 7(7), 754-760.
  • Newschaffer, C., Croen, L., & Daniels, J. (2007). The Epidemiology of Autism Spectrum Disorders. The Annual Review of Public Heath, 28, 234-258.
  • Newschaffer, C., & Curran, L. (2003). Autism: An Emerging Public Health Problem. Public Health Reports, 118(5), 393-399.
  • Smith, M. (2009). Nuclear and Mitochondrial Genome Defects in Autisms. Annals of the New York Academy of Sciences, 1151, 102-132.
  • Veenstra-VanderWeele, J., Christan, S., & Cook, E. (2004). Autism as a Paradigmatic Complex Genetic Disorder. The Annual Review of Genomics & Human Genetics, 5, 379-405.
  • Zhiling, Y., & Fujita, E. (2008). Mutations in the gene encoding CADM1 are associated with ASD. Biochemical and Biophysical Research Communications, 377, 926-929.