Whole-genome sequencing of quartet families with autism spectrum disorder

Yuen, Ryan K. C.; Thiruvahindrapuram, Bhooma; Merico, Daniele; Walker, Susan; Tammimies, Kristiina; Hoang, Ny; Chrysler, Christina; Nalpathamkalam, Thomas; Pellecchia, Giovanna; Liu, Yi; Gazzellone, Matthew J.; D’Abate, Lia; Deneault, Éric; Howe, Jennifer; Liu, Richard S C; Thompson, Ann; Zarrei, Mehdi; Uddin, Mohammed; Marshall, Christian R.; Ring, Robert H.; Zwaigenbaum, Lonnie; Ray, Peter N.; Weksberg, Rosanna; Carter, Melissa T.; Fernandez, Bridget A.; Roberts, Wendy; Szatmári, Péter; Scherer, Stephen W.

doi:10.1038/nm.3792

Cited by 487 publications

(438 citation statements)

References 58 publications

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“…Other studies suggest that mutations in the majority of siblings with ASD are on different genes, again suggesting that siblings share errors in the process of DNA replication and maintenance rather than inheriting a common mutation [60]. One common factor shared with siblings is the prenatal-maternal environment, which is increasingly being recognized as important for developmental outcomes [61].…”

Section: Folate Metabolism: An Example Of Environment-genome Interactionmentioning

confidence: 99%

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

2017

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Autism spectrum disorder (ASD) has been linked to abnormalities in folate metabolism. Polymorphisms in folate genes may act in complex polygenic ways to increase the risk of developing ASD. Autoantibodies that block folate transport into the brain have been associated with ASD and children with ASD and these autoantibodies respond to high doses of a reduced form of folate known as folinic acid (leucovorin calcium). Some of the same abnormalities are also found in mothers of children with ASD and supplementing folate during preconception and gestational periods reduces the risk to the offspring from developing ASD. These data suggest that folate pathway abnormalities may be a major metabolic disturbance underlying ASD that can be leveraged as biomarkers to improve symptoms and prevent ASD. Autism spectrum disorder: an emerging disorder with unclear etiology Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects about 2% of children in the USA [1]. Although it is defined through observation of the presence of abnormal behavior and absence of typical developmental milestones, ASD is associated with a wide range of medical abnormalities such as sleep, immune and gastrointestinal disorders and epilepsy. In addition to medical comorbidities, many children with ASD have disruptions in body physiology such as abnormalities in folate, cobalamin, tetrahydrobiopterin (BH 4 ), neurotransmitter, carnitine, redox and mitochondrial metabolism [2]. The connection between underlying physiological abnormalities and behavior is an area of active research. In this review, we will provide evidence that abnormalities of one-carbon folate metabolism are particularly important in ASD.Although the etiology of ASD is not known, genetics has been the focus of ASD research for many decades [3]. A notion of a pure genetic etiology is tempered by the fact that single gene and chromosomal defects are found in a minority of ASD cases, accounting for only 15.8% of cases when both chromosomal microarray and whole exome sequencing were used in one recent large study [4]. ASD has also been associated with exposures to numerous environmental agents during the prenatal and postnatal period [5]. Studies that have examined the contribution of the environmental and genetic components highlight that ASD arises as a consequence of complicated interactions between genetic predisposition and environmental factors [6,7]. As we will outline in this review, abnormalities in folate metabolism provide an excellent model of how environment factors can interact with genetic predisposition to cause ASD.At this time, the standard of care for ASD treatment is applied behavioral analysis and other equivalent behavioral interventions along with educational, developmental, occupational and speech therapy. Optimal application of behavioral therapy requires full-time one-on-one therapist for many years; however, even when this optimal therapy is applied, suboptimal outcomes are common. In addition, controlled studies examining the efficacy of variou...

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Section: Folate Metabolism: An Example Of Environment-genome Interactionmentioning

confidence: 99%

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

2017

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“…Base calling and analysis were performed using Illumina HiSeq Analysis Software v2‐2.5.55.1311. Reads were mapped to hg19 using Isaac alignment (SAAC00776.15.01.27) and single nucleotide and small indel variants called Isaac variant caller Starling 2.1.4.2 and annotated as previously described4 based on ANNOVAR 5. Copy number variants were detected as described by Trost et al6 Individuals I‐1, I‐2, II‐4, II‐6, II‐8, and II‐9 were also genotyped using Infinium HumanOmni2.5‐8 BeadChip according to the manufacture's protocol.…”

Section: Methodsmentioning

confidence: 99%

PI4K2A deficiency in an intellectual disability, epilepsy, myoclonus, akathisia syndrome

Alkhater

Scherer

Minassian

et al. 2018

Ann Clin Transl Neurol

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We report a family of Saudi Arabian ancestry with two children presenting with global developmental delay, dystonia, disturbed sleep, and heat intolerance. By genome sequencing, we identified a nonsense variant in the first exon of PI4K2A that was homozygous in both affected individuals and was absent from, or heterozygous in, seven unaffected siblings. PI4K2A is highly expressed in the brain and a mouse model displays a neurological phenotype, implicating PI4K2A as a new disease gene for a neurological disorder.

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“…Amazingly, however, there was as much cognitive and language variation within concordant MZ pairs as between pairs, including up to 50 IQ point discrepancy; regression also fails to show concordance in multiplex families (Parr et al, 2011). The opposite problem has also been demonstrated: Yuen et al (2015) did a GWA study of 85 families with two children affected by autism, focusing on genes previously associated with autism. They found that approximately 70% of the sibling pairs did not share an ASD-relevant mutation, but rather had different ones.…”

Section: Genotype-phenotype Relationshipsmentioning

confidence: 99%

Facilitating Autism Research

Fein

Helt

2017

J Int Neuropsychol Soc

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Early autism research focused on behavior and cognition. In recent decades, the pace of research has accelerated, and advances in imaging and genetics have allowed the accumulation of biological data. Nevertheless, a coherent picture of the syndrome at either phenotypic or biological level has not emerged. We see two fundamental obstacles to progress in basic understanding of autism. First, the two defining features (impairment in social interactions and communication, and restricted, repetitive behaviors and interests) are historically seen as integrally related. Others hold that these two major traits are fractionable and must be studied independently, casting doubt on autism as a coherent syndrome. Second, despite much recent research on brain structure and function, environmental factors, and genetics/genomics, findings on the biological level have not generally aligned well with those on the phenotypic level. In the first two sections, we explore these challenges, and in the third section, we review approaches that may facilitate progress, such as (1) including in studies all individuals defined by social impairment without regard to repetitive behaviors, (2) forming narrowly defined subtypes by thorough characterization on specific features, both diagnostic and non-diagnostic, (3) focusing on characteristics that may be relatively robust to environmental influence, (4) studying children as early as possible, minimizing environmental influence, and including longitudinal course as an important part of the phenotype, (5) subtyping by environmental risk factors, (6) distinguishing between what participants can do and what they typically do, and (7) aggregating large data sets across sites. (JINS, 2017, 23, 903-915)

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Whole-genome sequencing of quartet families with autism spectrum disorder

Cited by 487 publications

References 58 publications

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

PI4K2A deficiency in an intellectual disability, epilepsy, myoclonus, akathisia syndrome

Facilitating Autism Research

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