Dataset Information

Autistic Siblings with Novel Mutations in Two Different Genes: Insight for Genetic Workups of Autistic Siblings and Connection to Mitochondrial Dysfunction.

ABSTRACT: The prevalence of autism spectrum disorder (ASD) is high, yet the etiology of this disorder is still uncertain. Advancements in genetic analysis have provided the ability to identify potential genetic changes that may contribute to ASD. Interestingly, several genetic syndromes have been linked to metabolic dysfunction, suggesting an avenue for treatment. In this case study, we report siblings with ASD who had similar initial phenotypic presentations. Whole exome sequencing (WES) revealed a novel c.795delT mutation in the WDR45 gene affecting the girl, which was consistent with her eventual progression to a Rett-like syndrome phenotype including seizures along with a stereotypical cyclic breathing pattern. Interestingly, WES identified that the brother harbored a novel heterozygous Y1546H variant in the DEP domain-containing protein 5 (DEPDC5) gene, consistent with his presentation. Both siblings underwent a metabolic workup that demonstrated different patterns of mitochondrial dysfunction. The girl demonstrated statistically significant elevations in mitochondrial activity of complex I?+?III in both muscle and fibroblasts and increased respiration in peripheral blood mononuclear cells (PBMCs) on Seahorse Extracellular Flux analysis. The boy demonstrates a statistically significant decrease in complex IV activity in buccal epithelium and decreased respiration in PBMCs. These cases highlight the differences in genetic abnormalities even in siblings with ASD phenotypes as well as highlights the individual role of novel mutations in the WDR45 and DEPDC5 genes. These cases demonstrate the importance of advanced genetic testing combined with metabolic evaluations in the workup of children with ASD.

SUBMITTER: Burger BJ

PROVIDER: S-EPMC5643424 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Autistic Siblings with Novel Mutations in Two Different Genes: Insight for Genetic Workups of Autistic Siblings and Connection to Mitochondrial Dysfunction.

Burger Barrett J BJ Rose Shannon S Bennuri Sirish C SC Gill Pritmohinder S PS Tippett Marie L ML Delhey Leanna L Melnyk Stepan S Frye Richard E RE

Frontiers in pediatrics 20171012

The prevalence of autism spectrum disorder (ASD) is high, yet the etiology of this disorder is still uncertain. Advancements in genetic analysis have provided the ability to identify potential genetic changes that may contribute to ASD. Interestingly, several genetic syndromes have been linked to metabolic dysfunction, suggesting an avenue for treatment. In this case study, we report siblings with ASD who had similar initial phenotypic presentations. Whole exome sequencing (WES) revealed a novel ...[more]

PMID: 29075622

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Project description:PurposeCaregivers of autistic children present with high stress levels, which have been associated with poorer child outcomes in several domains, including language development. However, prior to this study, it was unknown whether elevated caregiver stress was associated with language development in infant siblings of autistic children (Sibs-autism), who are at increased likelihood of receiving a future diagnosis of autism and/or language impairment compared to infant siblings of non-autistic children. This study explored the degree to which, as well as the mechanisms by which, caregiver stress was linked with later language outcomes of Sibs-autism and infant siblings of non-autistic children (Sibs-NA).MethodParticipants were 50 infants (28 Sibs-autism; 22 Sibs-NA) aged 12-18 months at the first time point in this study (Time 1). Infants were seen again 9 months later, at 21-27 months of age (Time 2). Caregiver stress was measured via a validated self-report measure at Time 1. Caregiver language input, the putative mechanism by which caregiver stress may influence later language outcomes, was collected via two daylong recordings from digital recording (Language ENvironment Analysis) devices worn by the child at this same time point. Child language outcomes were measured via standardized and caregiver report measures at Time 2.ResultsSeveral models testing hypothesized indirect effects of caregiver stress on later child language outcomes through caregiver language input were statistically significant. Specifically, significant indirect effects suggest that (a) caregivers with increased stress tend to speak less to their infants, and (b) this reduced language input tends to covary with reduced child language outcomes later in life for Sibs-autism and Sibs-NA.ConclusionsThis study provides new insights into links between caregiver stress, caregiver language input, and language outcomes in Sibs-autism and Sibs-NA. Further work is necessary to understand how to best support caregivers and optimize the language learning environments for infants.Supplemental materialhttps://doi.org/10.23641/asha.21714368.

Dataset Information

Autistic Siblings with Novel Mutations in Two Different Genes: Insight for Genetic Workups of Autistic Siblings and Connection to Mitochondrial Dysfunction.

Publications

Autistic Siblings with Novel Mutations in Two Different Genes: Insight for Genetic Workups of Autistic Siblings and Connection to Mitochondrial Dysfunction.

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