Multiple-incidence Families Research Articles

Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families.

BackgroundPrevious studies have demonstrated aggregation of autistic traits in undiagnosed family members of children with autism spectrum disorder (ASD), which has significant implications for ASD risk in their offspring. This study capitalizes upon a large, quantitatively characterized clinical-epidemiologic family sample to establish the extent to which family transmission pattern and sex modulate ASD trait aggregation.MethodsData were analyzed from 5515 siblings (2657 non-ASD and 2858 ASD) included in the Interactive Autism Network. Autism symptom levels were measured using the Social Responsiveness Scale (SRS) and by computing Diagnostic and Statistical Manual of Mental Disorders—Fifth Edition (DSM-5) symptom scores based on items from the SRS and Social Communication Questionnaire. Generalized estimating equation models evaluated the influence of family incidence types (single versus multiple incidence families; male-only ASD-affected families versus families with female ASD-affected children), diagnostic group (non-ASD children with and without a history of language delay with autistic speech and ASD-affected children), and sibling sex on ASD symptom levels.ResultsNon-ASD children manifested elevated ASD symptom burden when they were members of multiple incidence families—this effect was accentuated for male children in female ASD-containing families—or when they had a history of language delay with autistic qualities of speech. In this sample, ASD-affected children from multiple incidence families had lower symptom levels than their counterparts in single incidence families. Recurrence risk for ASD was higher for children from female ASD-containing families than for children from male-only families.ConclusionsSex and patterns of family transmission modulate the risk of autism symptom burden in undiagnosed siblings of ASD-affected children. Identification of these symptoms/traits and their molecular genetic causes may have significant implications for genetic counseling and for understanding inherited liabilities that confer risk for ASD in successive generations. Autism symptom elevations were more dramatic in non-ASD children from multiple incidence families and those with a history of language delay and autistic qualities of speech, identifying sub-groups at substantially greater transmission risk. Higher symptom burden and greater recurrence in children from female ASD-containing families indicate that familial aggregation patterns are further qualified by sex-specific thresholds, supportive of the notion that females require a higher burden of deleterious liability to cross into categorical ASD diagnosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-015-0050-z) contains supplementary material, which is available to authorized users.

Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families

Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families

Advances in Our Understanding of Genetic Risk Factors for Autism Spectrum Disorders

Advances in Our Understanding of Genetic Risk Factors for Autism Spectrum Disorders

Sibling recurrence and the genetic epidemiology of autism.

Although the symptoms of autism exhibit quantitative distributions in nature, estimates of recurrence risk in families have never previously considered or incorporated quantitative characterization of the autistic phenotype among siblings. The authors report the results of quantitative characterization of 2,920 children from 1,235 families participating in a national volunteer register, with at least one child clinically affected by an autism spectrum disorder and at least one full biological sibling. A traditionally defined autism spectrum disorder in an additional child occurred in 10.9% of the families. An additional 20% of nonautism-affected siblings had a history of language delay, one-half of whom exhibited autistic qualities of speech. Quantitative characterization using the Social Responsiveness Scale supported previously reported aggregation of a wide range of subclinical (quantitative) autistic traits among otherwise unaffected children in multiple-incidence families and a relative absence of quantitative autistic traits among siblings in single-incidence families. Girls whose standardized severity ratings fell above a first percentile severity threshold (relative to the general population distribution) were significantly less likely to have elicited community diagnoses than their male counterparts. These data suggest that, depending on how it is defined, sibling recurrence in autism spectrum disorder may exceed previously published estimates and varies as a function of family type. The results support differences in mechanisms of genetic transmission between simplex and multiplex autism and advance current understanding of the genetic epidemiology of autism spectrum conditions.

Autistic Social Impairment in the Siblings of Children With Pervasive Developmental Disorders

Sibling recurrence risk in autism has been estimated to be approximately 10%. This study investigated subsyndromal autistic impairments among siblings of probands with pervasive developmental disorders. The authors used the Social Responsiveness Scale to obtain quantitative assessments of autistic social impairment in three groups of proband-sibling pairs: 1) autistic children from multiple-incidence families and their closest in age nonautistic brothers (N=49 pairs); 2) children with any pervasive developmental disorder, including autism, and their closest-in-age brothers (N=100 pairs), and 3) children with psychopathology unrelated to autism and their closest-in-age brothers (N=45 pairs). Sibling Social Responsiveness Scale scores were continuously distributed and substantially elevated for both the autistic and pervasive developmental disorder groups. Highest scores (i.e., greatest impairment) were seen among siblings of autistic probands from multiple-incidence families, followed by siblings of probands with any pervasive developmental disorder, then siblings of probands with psychopathology unrelated to autism. Taken together with previous findings, these results support the notion that genetic susceptibility factors responsible for common, subsyndromal social impairments may be related to the causes of categorically defined pervasive developmental disorders.

Bipolar disorder and the pseudoautosomal region: an association study.

From family, adoption, and twin studies it is clear that genetic factors play an important role in the etiology of bipolar disorder (McGuffin and Katz: The Biology of Depression, Gaskell, London, 1986). Recently Yoneda et al. (Am J Hum Genet 51:1172-1173, 1992) reported an association between an allele (A4) of a VNTR marker (DXYS20) for the pseudoautosomal region and bipolar disorder in a Japanese population. In order to test for this association in a Caucasian population, we have typed a sample of 52 subjects with bipolar disorder and 61 normal controls. The bipolar subjects are probands of multiple incidence families. The normal controls are an epidemiologically ascertained sample of middle-aged, unrelated individuals. The two groups were matched for sex and ethnic background. There were no significant differences in the allele or genotype frequencies of DXYS20 between the two groups. In particular, there was no significant difference in the frequency of the A4 allele in normal controls and bipolar patients (0.377 vs. 0.317, respectively). The prevalence of the A4 allele in bipolar patients and normal controls was 0.567 and 0.622, respectively. We were not able to replicate the results of the Yoneda et al. (1992) study.

A Report of One Family With Four Autistic Siblings and Four Families With Three Autistic Siblings

This is the first report of four autistic siblings. Four previously unreported families with three autistic siblings are also described. Careful review of pre-, peri-, and postnatal medical data failed to reach any common potentially pathological events in these 16 autistic siblings or their families. Taken together with other recently documented multiple incidence families, they are consistent with the possibility of a genetically determined type of autism.

Pre-, Peri-, and Postnatal Factors in 181 Autistic Patients from Single and Multiple Incidence Families

The incidence of 34 potentially pathologic pre-, peri-, neo-, and postnatal factors in the first 181 patients enrolled in the UCLA Registry for Genetic Studies of Autism was determined. Mothers of autistic patients from single ( N = 75) incidence families had significantly increased incidences of bleeding, flu-like symptoms, taking medications during pregnancy, and induced labors than multiple incidences cases ( N = 106). Boys ( N = 149) and girls ( N = 32) were equally impaired on IQ tests.