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Genetics of FASD: Confounding Rare Craniofacial and Neurodevelopmental Disorders May Identify Ethanol-Sensitizing Genetic Variants of FASD

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Fetal Alcohol Spectrum Disorder

Part of the book series: Neuromethods ((NM,volume 188))

Abstract

Fetal alcohol spectrum disorder (FASD) is a clinically diverse teratogenic disorder with many underlying contributing risk factors including other environmental influences and temporal, epigenetic, and genetic factors. Twin studies of children with FASD have established a genetic component to the disorder; however, identifying which genes and their variants contribute to the pathogenesis of this complex and common disorder remains elusive. In this chapter, we highlight the genetic determinants of rare neurodevelopmental disorders that share overlapping clinical phenotypes to FASD, including CHARGE, Aarskog, Smith-Lemli-Optiz, Opitz-Kaveggia, Campomelic dysplasia, Noonan, Cornelia de Lange, and 22q11.2 deletion syndrome (DS). We hypothesize that by examining the genetic determinants of these rare developmental disorders, we can identify potential prenatal alcohol exposure susceptibility genes of FASD. Indeed, our investigation identified many specific candidate genes in neurodevelopmental signaling pathways that are well established in animal models of FASD-like outcomes following prenatal alcohol exposure, including those in the RAS/MAPK, Wnt/Ca2+, SHH, cholesterol, and retinoic acid pathways. Our findings support the notion that causative alleles of these rare developmental disorders may be sensitizing to prenatal alcohol exposure outcomes as seen in FASD. Sensitization by prenatal alcohol exposure could result in a direct functional modulation of protein activity or induction of an epigenetic modulation of candidate gene expression and define new underlying etiologies of FASD. Moreover, the frequency of PAE-sensitizing variants should be enriched in children with FASD and may provide new FASD diagnostic biomarkers.

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Abbreviations

22q11.2DS :

22q11.2 Deletion syndrome

7-DHC:

7-dehydrocholestrol

BMP:

Bone morphogenetic protein

Ca2+:

Calcium

CamK:

Calcium and calmodulin-dependent kinase

CAV:

Caveolin

CdLS :

Cornelia de Lange syndrome

FASD :

Fetal alcohol spectrum disorder

FGF:

Fibroblast growth factor

LCR:

Low-copy number repeats

MED :

Mammalian mediator complex

NCC :

Neural crest cells

NS :

Noonan syndrome

PAE :

Prenatal alcohol exposure

PTCH:

Patched

RA :

Retinoic acid

RAR:

Retinoic acid receptor

SHH :

Sonic hedgehog

SLOS :

Smith-Lemli-Opitz syndrome

SMO:

Smoothened

TGF-β:

Transforming growth factor β

WNT :

Wingless/integrated

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Acknowledgments

We wish to thank Abraham Fainsod, Songyan Liu, and Molly Pind for enlightening and provocative discussions over the years that contributed to this manuscript.

Funding

This work was funded in part by grants to GGH from the Canadian Institutes of Health Research (PJT-165847), Manitoba Liquor & Lotteries Corporation (55201 and 55380), and Kids Brain Health Network (48694) and to LM from the Kids Brain Health Network (54525).

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  1. Authors “Leo McKay” and “Berardino Petrelli” contributed equally to this chapter.

Authors and Affiliations

  1. Department of Biochemistry & Medical Genetics, Regenerative Medicine Program, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

    Leo McKay, Berardino Petrelli & Geoffrey G. Hicks

  2. Department of Pediatrics and Child Health, Max Rady College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

    Albert E. Chudley

  3. Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

    Albert E. Chudley

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  1. Leo McKay
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Correspondence to Geoffrey G. Hicks .

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Editors and Affiliations

  1. Dept. of Pediatrics and Child Health and Dept. of Biochem & Med. Genetics, University of Manitoba, Winnipeg, MB, Canada

    Albert E. Chudley

  2. Dept. of Biochem & Med. Genetics, Regenerative Medicine Program, University of Manitoba, Winnipeg, MB, Canada

    Geoff G. Hicks

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McKay, L., Petrelli, B., Chudley, A.E., Hicks, G.G. (2022). Genetics of FASD: Confounding Rare Craniofacial and Neurodevelopmental Disorders May Identify Ethanol-Sensitizing Genetic Variants of FASD. In: Chudley, A.E., Hicks, G.G. (eds) Fetal Alcohol Spectrum Disorder. Neuromethods, vol 188. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2613-9_5

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