Anne B Arnett1,2, Jennifer S Beighley1,2, Evangeline C Kurtz-Nelson1,2, Kendra Hoekzema3, Tianyun Wang3, Raphe A Bernier1, Evan E Eichler3,4. 1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA. 2. Center on Human Development and Disability, University of Washington, Seattle, Washington, USA. 3. Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. 4. Howard Hughes Medical Institute, Seattle, Washington, USA.
Abstract
Approximately one-fourth of autism spectrum disorder (ASD) cases are associated with a disruptive genetic variant. Many of these ASD genotypes have been described previously, and are characterized by unique constellations of medical, psychiatric, developmental, and behavioral features. Development of precision medicine care for affected individuals has been challenging due to the phenotypic heterogeneity that exists even within each genetic subtype. In the present study, we identify developmental milestones that predict cognitive and adaptive outcomes for five of the most common ASD genotypes. Sixty-five youth with a known pathogenic variant involving ADNP, CHD8, DYRK1A, GRIN2B, or SCN2A genes participated in cognitive and adaptive testing. Exploratory linear regressions were used to identify developmental milestones that predicted cognitive and adaptive outcomes within each gene group. We hypothesized that the earliest and most predictive milestones would vary across gene groups, but would be consistent across outcomes within each genetic subtype. Within the ADNP group, age of walking predicted cognitive outcomes, while age of first words predicted adaptive behaviors. Age of phrases predicted adaptive functioning in the CHD8 group, but cognitive outcomes were not clearly associated with early developmental milestones. Verbal milestones were the strongest predictors of cognitive and adaptive outcomes for individuals with mutations to DYRK1A, GRIN2B, or SCN2A. These trends inform decisions about treatment planning and long-term expectations for affected individuals, and they add to the growing body of research linking molecular genetic function to brain development and phenotypic outcomes. LAY SUMMARY: Researchers have found many genetic causes of autism including mutations to ADNP, CHD8, DYRK1A, GRIN2B, and SCN2A genes. We found that each genetic cause had different early developmental milestones that explained the overall functioning of the children when they were older. Depending on the genetic cause, the age that a child first starts walking and/or talking may help to better understand and support a child's development who has a mutation to one of the above genes. Autism Res 2020, 13: 1659-1669.
Approximately one-fourth of autism spectrum disorder (ASD) cases are associated with a disruptive genetic variant. Many of these ASD genotypes have been described previously, and are characterized by unique constellations of medical, psychiatric, developmental, and behavioral features. Development of precision medicine care for affected individuals has been challenging due to the phenotypic heterogeneity that exists even within each genetic subtype. In the present study, we identify developmental milestones that predict cognitive and adaptive outcomes for five of the most common ASD genotypes. Sixty-five youth with a known pathogenic variant involving ADNP, CHD8, DYRK1A, GRIN2B, or SCN2A genes participated in cognitive and adaptive testing. Exploratory linear regressions were used to identify developmental milestones that predicted cognitive and adaptive outcomes within each gene group. We hypothesized that the earliest and most predictive milestones would vary across gene groups, but would be consistent across outcomes within each genetic subtype. Within the ADNP group, age of walking predicted cognitive outcomes, while age of first words predicted adaptive behaviors. Age of phrases predicted adaptive functioning in the CHD8 group, but cognitive outcomes were not clearly associated with early developmental milestones. Verbal milestones were the strongest predictors of cognitive and adaptive outcomes for individuals with mutations to DYRK1A, GRIN2B, or SCN2A. These trends inform decisions about treatment planning and long-term expectations for affected individuals, and they add to the growing body of research linking molecular genetic function to brain development and phenotypic outcomes. LAY SUMMARY: Researchers have found many genetic causes of autism including mutations to ADNP, CHD8, DYRK1A, GRIN2B, and SCN2A genes. We found that each genetic cause had different early developmental milestones that explained the overall functioning of the children when they were older. Depending on the genetic cause, the age that a child first starts walking and/or talking may help to better understand and support a child's development who has a mutation to one of the above genes. Autism Res 2020, 13: 1659-1669.
Authors: Konrad Platzer; Hongjie Yuan; Hannah Schütz; Alexander Winschel; Wenjuan Chen; Chun Hu; Hirofumi Kusumoto; Henrike O Heyne; Katherine L Helbig; Sha Tang; Marcia C Willing; Brad T Tinkle; Darius J Adams; Christel Depienne; Boris Keren; Cyril Mignot; Eirik Frengen; Petter Strømme; Saskia Biskup; Dennis Döcker; Tim M Strom; Heather C Mefford; Candace T Myers; Alison M Muir; Amy LaCroix; Lynette Sadleir; Ingrid E Scheffer; Eva Brilstra; Mieke M van Haelst; Jasper J van der Smagt; Levinus A Bok; Rikke S Møller; Uffe B Jensen; John J Millichap; Anne T Berg; Ethan M Goldberg; Isabelle De Bie; Stephanie Fox; Philippe Major; Julie R Jones; Elaine H Zackai; Rami Abou Jamra; Arndt Rolfs; Richard J Leventer; John A Lawson; Tony Roscioli; Floor E Jansen; Emmanuelle Ranza; Christian M Korff; Anna-Elina Lehesjoki; Carolina Courage; Tarja Linnankivi; Douglas R Smith; Christine Stanley; Mark Mintz; Dianalee McKnight; Amy Decker; Wen-Hann Tan; Mark A Tarnopolsky; Lauren I Brady; Markus Wolff; Lutz Dondit; Helio F Pedro; Sarah E Parisotto; Kelly L Jones; Anup D Patel; David N Franz; Rena Vanzo; Elysa Marco; Judith D Ranells; Nataliya Di Donato; William B Dobyns; Bodo Laube; Stephen F Traynelis; Johannes R Lemke Journal: J Med Genet Date: 2017-04-04 Impact factor: 6.318
Authors: Somer L Bishop; Cristan Farmer; Vanessa Bal; Elise B Robinson; A Jeremy Willsey; Donna M Werling; Karoline Alexandra Havdahl; Stephan J Sanders; Audrey Thurm Journal: Am J Psychiatry Date: 2017-03-03 Impact factor: 18.112
Authors: Stephan J Sanders; Arthur J Campbell; Jeffrey R Cottrell; Rikke S Moller; Florence F Wagner; Angie L Auldridge; Raphael A Bernier; William A Catterall; Wendy K Chung; James R Empfield; Alfred L George; Joerg F Hipp; Omar Khwaja; Evangelos Kiskinis; Dennis Lal; Dheeraj Malhotra; John J Millichap; Thomas S Otis; Steven Petrou; Geoffrey Pitt; Leah F Schust; Cora M Taylor; Jennifer Tjernagel; John E Spiro; Kevin J Bender Journal: Trends Neurosci Date: 2018-04-23 Impact factor: 13.837
Authors: Brian J O'Roak; Laura Vives; Santhosh Girirajan; Emre Karakoc; Niklas Krumm; Bradley P Coe; Roie Levy; Arthur Ko; Choli Lee; Joshua D Smith; Emily H Turner; Ian B Stanaway; Benjamin Vernot; Maika Malig; Carl Baker; Beau Reilly; Joshua M Akey; Elhanan Borenstein; Mark J Rieder; Deborah A Nickerson; Raphael Bernier; Jay Shendure; Evan E Eichler Journal: Nature Date: 2012-04-04 Impact factor: 49.962
Authors: B J O'Roak; H A Stessman; E A Boyle; K T Witherspoon; B Martin; C Lee; L Vives; C Baker; J B Hiatt; D A Nickerson; R Bernier; J Shendure; E E Eichler Journal: Nat Commun Date: 2014-11-24 Impact factor: 14.919
Authors: Jennifer S Beighley; Caitlin M Hudac; Anne B Arnett; Jessica L Peterson; Jennifer Gerdts; Arianne S Wallace; Heather C Mefford; Kendra Hoekzema; Tychele N Turner; Brian J O'Roak; Evan E Eichler; Raphael A Bernier Journal: Biol Psychiatry Date: 2019-07-30 Impact factor: 13.382
Authors: Raphael Bernier; Christelle Golzio; Bo Xiong; Holly A Stessman; Bradley P Coe; Osnat Penn; Kali Witherspoon; Jennifer Gerdts; Carl Baker; Anneke T Vulto-van Silfhout; Janneke H Schuurs-Hoeijmakers; Marco Fichera; Paolo Bosco; Serafino Buono; Antonino Alberti; Pinella Failla; Hilde Peeters; Jean Steyaert; Lisenka E L M Vissers; Ludmila Francescatto; Heather C Mefford; Jill A Rosenfeld; Trygve Bakken; Brian J O'Roak; Matthew Pawlus; Randall Moon; Jay Shendure; David G Amaral; Ed Lein; Julia Rankin; Corrado Romano; Bert B A de Vries; Nicholas Katsanis; Evan E Eichler Journal: Cell Date: 2014-07-03 Impact factor: 41.582
Authors: Holly A F Stessman; Bo Xiong; Bradley P Coe; Tianyun Wang; Kendra Hoekzema; Michaela Fenckova; Malin Kvarnung; Jennifer Gerdts; Sandy Trinh; Nele Cosemans; Laura Vives; Janice Lin; Tychele N Turner; Gijs Santen; Claudia Ruivenkamp; Marjolein Kriek; Arie van Haeringen; Emmelien Aten; Kathryn Friend; Jan Liebelt; Christopher Barnett; Eric Haan; Marie Shaw; Jozef Gecz; Britt-Marie Anderlid; Ann Nordgren; Anna Lindstrand; Charles Schwartz; R Frank Kooy; Geert Vandeweyer; Celine Helsmoortel; Corrado Romano; Antonino Alberti; Mirella Vinci; Emanuela Avola; Stefania Giusto; Eric Courchesne; Tiziano Pramparo; Karen Pierce; Srinivasa Nalabolu; David G Amaral; Ingrid E Scheffer; Martin B Delatycki; Paul J Lockhart; Fereydoun Hormozdiari; Benjamin Harich; Anna Castells-Nobau; Kun Xia; Hilde Peeters; Magnus Nordenskjöld; Annette Schenck; Raphael A Bernier; Evan E Eichler Journal: Nat Genet Date: 2017-02-13 Impact factor: 38.330