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Examining Genes to Describe Different Types of Autism

Marina Sarris
Interactive Autism Network at Kennedy Krieger Institute
Date Published: 
March 20, 2018

Scientists and families alike often wonder how autism can look so different in different people. Why does one person have trouble learning and speaking, while another person with the same condition speaks fluently and has an advanced degree?

Is the answer buried somewhere in our genetic code? One group of researchers wanted to see if they could identify a subtype of autism by examining genes.1 They looked to the families in the Simons Simplex Collection (SSC) autism research project, which has 2,600 families who each have one child with autism. The families contributed genetic samples and information about their child's autistic symptoms and developmental history, which allowed scientists to compare symptoms and genetic makeup.

Led by Somer L. Bishop, PhD, at University of California, San Francisco, researchers looked for children who have certain genetic changes that are believed to be linked to autism. Those changes were mutations that caused a gene to lose some of its functioning, as well as Copy Number Variants, called CNVs. A CNV is a missing or extra piece of a chromosome. Newer tests, such as the chromosomal microarray, can uncover these small alterations to a chromosome. Someone with a CNV may have a missing or extra gene or genes.

They found 112 children with one of these mutations in the SSC, a project of the Simons Foundation Autism Research Initiative. Thanks to having genetic samples from parents, the researchers knew that these changes were new ("de novo"), and not inherited from mothers or fathers.

Matching Children on Age, Sex, and IQ

This is not the first study to investigate genetic changes in the SSC children. But it is believed to be the first to take one extra step.1 Dr. Bishop's team wanted to make sure that its results were not affected by something other than genetics. Autism symptoms, for examples, are "strongly influenced" by IQ,1, 2 so researchers decided to account for that. The children with genetic mutations tended to have lower cognitive abilities and daily living skills than the SSC group as a whole. For this study, the researchers matched each of the 112 children with another SSC child of the same sex, age, and similar nonverbal IQ. That left only one major difference between the two groups of children with autism: half have a suspicious genetic mutation, and half have no mutations at all.

When they compared the two groups on autism symptoms, they found differences that may seem surprising. The children with mutations had better verbal and language ability, and a greater likelihood of having fluent language, than the children without mutations. They had a smaller gap between their nonverbal and verbal IQ scores. The children with these mutations appear to have a "muted" profile of symptoms in the areas of language and social communication.1 Interestingly, the clinicians who had diagnosed them were less certain of their autism diagnosis than the comparison children. Nonetheless, they all met the criteria for autism spectrum disorder (ASD), Dr. Bishop said.

"The kids with de novo mutations look less severely affected on certain measures of autism," she said. "There are other factors at play when you compare these children to other kids with ASD who don’t have any identifiable, rare mutations of the type we were studying," explained Dr. Bishop, a clinical psychologist who specializes in autism. "We have multiple roads leading to autism, and sometimes it can be a combination of factors."

Late Walkers and Genetic Changes

The later age of walking is not surprising.

The children with mutations did have another notable difference from the comparison group: they took their first steps several months later, between 14.7 and 19 months of age. (Most children who are developing typically take their first steps around 12 months. However, "it's perfectly normal for children to start walking a little earlier or later," according to the American Academy of Pediatrics.3) Dr. Bishop's team concluded that the age at which a child with autism learns to walk by himself could be a clue of a "potential genetic abnormality."1

The link between late walking and genetic conditions is not new. Delayed motor skills are often seen in children with genetic disorders such as velocardiofacial, Fragile X, and Noonan syndromes.4 Late walking also is more common in children with intellectual disability, compared to typically developing children and children with autism.1, 5 Autism is more common in people with certain genetic conditions, such as Fragile X, Down, and Phelan-McDermid syndromes and tuberous sclerosis, than in the general population.

"The later age of walking is not surprising," Dr. Bishop said. "A gross motor milestone delay is very common in kids with genetic syndromes, with or without ASD. In that regard, kids with a de novo mutation look more like kids with a genetic syndrome and autism, than kids without a genetic syndrome, and autism."

Another Study Finds Broader Motor Delays

Another study of SSC children also found a link between new (not inherited) genetic mutations and problems with motor skills. This study examined gross motor skills, such as running, walking, and jumping, and fine motor or hand skills. Led by Michael Wigler, professor at Cold Spring Harbor Laboratory in New York, the researchers looked at more types of genetic mutations, including one that is generally considered less severe. This mutation, called a "missense," involves a change to a single chemical that makes up a tiny part of one gene.6

More severe mutations generally lead to delays and problems with motor skills in people with autism, the team concluded. Lower IQ has been linked to genetic mutations,7 but this link is not as pronounced as the one to motor skills. For example, the researchers noted, it is rare for someone with autism to have low nonverbal intelligence and "normal" motor skills. But it is not unusual to have a "normal" IQ and poor motor skills.6

The team also concluded that mutations do not appear to influence the core symptoms of autism, namely problems with social communication and repetitive behaviors. Dr. Wigler's team did not find that children with mutations had a muted form of ASD, one conclusion of Dr. Bishop's study.

The two, independent research teams used different methods to study the SSC children. Nonetheless, both found a link between new mutations and motor skill problems. This link should reinforce the need to evaluate motor skills in children who are being assessed for autism, according to Dr. Wigler's team. This should not be too burdensome. After all, "motor skills are simple to measure."6

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Additional Resources: 
  1. Bishop SL, Farmer C, Bal V, et al. Identification of developmental and behavioral markers associated with genetic abnormalities in autism spectrum disorder. Am J Psychiatry. 2017;174(6):576-585. Abstract.
  2. Havdahl KA, Bal VH, Huerta M, et al. Multidimensional influences on autism symptom measures: Implications for use in etiological research. J Am Acad Child Adolesc Psychiatry. 2016;55(12):1054-1063.e3. Abstract.
  3. American Academy of Pediatrics. Caring for your baby and young child: Birth to age 5, movement: 8 to 12 months. Updated 2009. Accessed February 28, 2018.
  4. Noritz GH, Murphy NA, Neuromotor Screening Expert Panel. Motor delays: Early identification and evaluation. Pediatrics. 2013;131(6):e2016-27. Abstract.
  5. Bishop SL, Thurm A, Farmer C, Lord C. Autism spectrum disorder, intellectual disability, and delayed walking. Pediatrics. 2016;137(3):e20152959-2959. Epub 2016 Feb 3. Abstract.
  6. Buja A, Volfovsky N, Krieger AM, et al. Damaging de novo mutations diminish motor skills in children on the autism spectrum. Proc Natl Acad Sci U S A. 2018;115(8):E1859-E1866. Abstract.
  7. O'Roak BJ, Deriziotis P, Lee C, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011;43(6):585-589. Abstract.