Recurrence of Autism in Families

“I am a parent of a young boy with autism. I don’t know of any other individuals in my family with an autism diagnosis but am considering having more children. How likely is it that I could have another child with autism?”

Answered by Scott M. Myers, MD, FAAP, Neurodevelopmental Pediatrician, Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA.

This important question is asked by many parents who are considering having more children. The answer depends greatly on whether a specific genetic cause of your child’s autism spectrum disorder (ASD) has been identified. Currently, genetic testing can identify a specific cause in approximately 15% of children with ASD, and this information allows more accurate counseling about recurrence risk for the individual family. In instances where a genetic cause is unknown, different types of studies have found varying rates of recurrence risk.

Epidemiologic studies investigate the characteristics of diseases or disorders in large populations using rigorous statistical methods. These studies have found that 4-7% of families had more than one child with an ASD (Chakrabarti & Fombonne, 2001; Gronborg, Schendel, & Parner, 2013). The largest and most recent population-based study, which included over 1.5 million children born in Denmark between 1980 and 2004, found an overall recurrence risk of 7% (Gronborg et al., 2013). This type of study has many advantages, such as avoiding bias introduced by increased parental awareness and differential participation when there is already a child with an ASD in the family. However, this type of study design may lead to underestimation of recurrence risk because of missed cases in the populations studied and the tendency of couples with an affected child to stop having children, which is known as “stoppage.”

Rather than including all children in a given region, some research focuses only on children with ASD and their siblings. Studies that include all siblings born before and after the child who has ASD have found the ASD recurrence risk to be 6-10% (Bolton et al., 1994; Chudley, Guitierrez, Jocelyn, & Chodirker. 1998; Sumi, Taniai, Miyachi, & Tanemura, 2006); however, like epidemiologic studies, they may underestimate recurrence risk due to stoppage. Studies that only include families with later-born siblings to avoid the stoppage effect have reported higher recurrence rates of 8-19% (Constantino, Zhang, Frazier, Abbacchi, & Law, 2010; Ozonoff et al., 2011; Ritvo, Jorde, Mason-Brothers, Freeman, Pingree, Jones, & Mo, 1989). The highest rate of recurrence, almost 19%, was found in a large, prospective study of younger siblings of children with an ASD who were recruited in infancy and monitored closely (Ozonoff et al., 2011). However, when families that already had two or more children with ASD were excluded, the recurrence rate was 13.5% in this study.

Therefore, the short answer is that for a couple with one child with ASD of unknown cause, the current best estimate of recurrence in a subsequent child is approximately 10% based on the most recent and well-designed studies. Because this is much higher than the 1% chance of any random couple in the general population having a child with ASD, the younger siblings of a child with ASD should be monitored closely and screened for ASD at well-child visits as recommended by the American Academy of Pediatrics (Johnson, Myers, & Council on Children With Disabilities, 2007). If a couple already has two or more children with an ASD, the chance of a subsequent child having an ASD may be as high as 32-35% (Ozonoff et al., 2011; Ritvo et al., 1989).

Two other points related to recurrence rates are worth noting. First, some studies have suggested that the risk of ASD in later-born children is higher if the first affected child was a girl and lower if the first affected child was a boy (Ritvo et al., 1989; Jorde et al., 1991; Sumi et al., 2006). Conversely, other more recent studies have not found that the sex of the first affected child is associated with a significant difference in recurrence risk in subsequent children (Goin-Kochel et al., 2007; Constantino et al., 2010; Ozonoff et al., 2011). Thus, at present, the available evidence does not argue convincingly for adjusting recurrence risk based on the sex of the first child with ASD. Second, some studies have found that 20-25% of siblings who do not meet criteria for an ASD do have a history of language impairment or delay (Constantino et al., 2010; Lindgren, Folstein, Tomblin, & Tager-Flusberg, 2009). The risk of language delay in a subsequent child is not included within the ASD recurrence rate estimates reported above.

It is important to understand that the recurrence estimates measured in these studies are based on group averages and that unless the specific genetic cause of the first child’s ASD is known, it is not possible for a family to receive specific counseling about their individual level of risk. This is one reason why it is important that families be offered genetic testing for their child with ASD. When the physician does not suspect a specific disorder or syndrome based on examination, the current recommendation is to complete chromosomal microarray analysis and Fragile X molecular analysis (Manning & Hudgins, 2010; Miller et al., 2010). These tests, which are typically performed on a blood sample obtained from the affected child, identify a specific cause in approximately 15% of individuals with ASD, and this number is likely to increase as newer technologies such as whole exome sequencing and whole genome sequencing become more widely available and utilized for clinical purposes (Abrahams & Geshwind, 2008; O’Roak, et al., 2012; Sanders et al., 2012).

For families in which a genetic cause of ASD has been identified, the recurrence risk varies significantly depending on the type of genetic problem found. For example, the risk could be as high as 50%, as in the case of a child who inherits a specific extra segment of DNA on the 15th chromosome (15q11-q13) from his/her mother. Or, the recurrence risk could be as low as 1% or less if the child has a small “missing” or “extra” section of DNA (called a microdeletion or microduplication) that is not carried by either parent.

It is also important to understand that if a specific cause is not found upon genetic testing, it does not mean that the cause is not genetic, just that it cannot be identified currently using the tests that were completed.

In summary, for a couple with one child with an ASD of unknown cause, the current best estimate of the risk of a subsequent child having ASD is approximately 10% based on group averages. Any couple with questions about recurrence risk should pursue genetic counseling so that the information can be tailored to their specific situation. Because of the increased risk of ASD, all younger siblings of an affected child should be monitored through routine administration of ASD screening tools to facilitate earlier identification and intervention.

For a more detailed article on this topic, please see http://www.asatonline.org/resources/clinician/morechildren.htm

References

Abrahams, B. S., & Geschwind, D. H. (2008). Advances in autism genetics: On the threshold of a new neurobiology. Nature Reviews Genetics, 9, 341-355.

Bolton, P., Macdonald, H., Pickles, A., Rios, P., Goode, S., Crowson, M.,Rutter, M. (1994). A case-control family history study of autism. Journal of Child Psychology & Psychiatry & Allied Disciplines, 35, 877-900.

Chakrabarti, S., & Fombonne, E. (2001). Pervasive developmental disorders in preschool children. JAMA, 285, 3093-3099.

Chudley, A. E., Guitierrez, E., Jocelyn, L. J., & Chodirker, B. N. (1998). Outcomes of genetic evaluation in children with pervasive developmental disorder. Journal of Developmental and Behavioral Pediatrics, 19, 321-325.

Constantino, J. N., Zhang, Y., Frazier, T., Abbacchi, A. M., & Law, P. (2010). Sibling recurrence and the genetic epidemiology of autism. American Journal of Psychiatry, 167, 1349-1356.

Goin-Kochel, R. P., Abbacchi, A., Constantino, J. N., & Autism Genetic Resource Exchange Consortium. (2007). Lack of evidence for increased genetic loading for autism among families of affected females: A replication from family history data in two large samples. Autism, 11,279-286.

Gronborg, T. K., Schendel, D. E., & Parner, E. T. (2013). Recurrence of Autism Spectrum Disorders in Full- and Half-Siblings and Trends Over Time: A Population-Based Cohort Study. JAMA Pediatrics, 2259, E1-E7, doi:10.1001/jamapediatrics.2013.2259.

Johnson, C.P., Myers, S.M., & Council on Children with Disabilities. (2007). Identification and evaluation of children with autism spectrum disorders. Pediatrics, 120, 1183-1215.

Jorde, L.B., Hasstedt, S. J., Ritvo, E. R., Mason-Brothers, A., Freeman, B. J., Pingree, C., Mo, A. (1991). Complex segregation analysis of autism. American Journal of Human Genetics, 49,932-938.

Lindgren, K. A., Folstein, S. E., Tomblin, J. B., & Tager-Flusberg, H. (2009). Language and reading abilities of children with autism spectrum disorders and specific language impairment and their first degree relatives. Autism Research, 2, 22-38.

Manning, M., & Hudgins, L. (2010). Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genetics in Medicine, 12, 742-745.

Miller, D. T., Adam, M. P., Aradhya, S., Biesecker, L. G., Brothman, A. R., Carter, N. P.,Ledbetter, D. H. (2010). Consensus statement: Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American Journal of Human Genetics, 86, 749-764.

O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Eichler, E. E. (2012).Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 485, 246-250.

Ozonoff, S., Young, G. S., Carter, A., Messinger, D., Yirmiya, N., Zwaigenbaum, L., Stone, W.L. (2011). Recurrence risk for autism spectrum disorders: A baby siblings research consortium study. Pediatrics, 128:e488-e495.

Ritvo, E. R., Jorde, L. B., Mason-Brothers, A., Freeman, B. J., Pingree, C., Jones, M. B., & Mo, A. (1989). The UCLA- University of Utah epidemiologic survey of autism: Recurrence risk estimates and genetic counseling. American Journal of Psychiatry, 146, 1032-1036.

Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., State, M.W. (2012). De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature, 485, 237-241.

Sumi, S., Taniai, H., Miyachi, T., & Tanemura, M. (2006). Sibling risk of pervasive developmental disorder estimated by means of an epidemiologic survey in Nagoya, Japan. Journal of Human Genetics, 51, 518-522.