Haploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome

Abigail U Carbonell,Jaafar O Tindi,Alana Iaboni,Stephen W Scherer,Thomas A Neubert,Ifat Kvint,Chang Hoon Cho,Evdokia Anagnostou,Hediye Erdjument-Bromage,Ehud Banne,Juliana C Bates,Bryen A Jordan,Svetlana Cvejic,Jenny Rosensaft,Sophie Molholm,Pamela A Counts

doi:10.1038/s41467-019-11437-w

Abstract

Neurodevelopmental disorders, including autism spectrum disorder, have complex polygenic etiologies. Single-gene mutations in patients can help define genetic factors and molecular mechanisms underlying neurodevelopmental disorders. Here we describe individuals with monogenic heterozygous microdeletions in ANKS1B, a predicted risk gene for autism and neuropsychiatric diseases. Affected individuals present with a spectrum of neurodevelopmental phenotypes, including autism, attention-deficit hyperactivity disorder, and speech and motor deficits. Neurons generated from patient-derived induced pluripotent stem cells demonstrate loss of the ANKS1B-encoded protein AIDA-1, a brain-specific protein highly enriched at neuronal synapses. A transgenic mouse model of Anks1b haploinsufficiency recapitulates a range of patient phenotypes, including social deficits, hyperactivity, and sensorimotor dysfunction. Identification of the AIDA-1 interactome using quantitative proteomics reveals protein networks involved in synaptic function and the etiology of neurodevelopmental disorders. Our findings formalize a link between the synaptic protein AIDA-1 and a rare, previously undefined genetic disease we term ANKS1B haploinsufficiency syndrome.

Highlights

Neurodevelopmental disorders, including autism spectrum disorder, have complex polygenic etiologies
We identified two families (EIN-1 and Einstein College of Medicine (EIN)-2) harboring monogenic microdeletions in ANKS1B who had been referred for medical genetic evaluation due to various neurodevelopmental disorders, including autism, attention-deficit/hyperactivity disorder (ADHD), speech apraxia, and motor delays (Table 1)
Verbal impairments were more severe in female children (EIN-1-2 and EIN-2-1), consistent with their prior diagnosis of speech apraxia, and manifested in lower scores in Verbal Comprehension Index (VCI), expressive language, receptive language, and verbal memory compared to males

Summary

Introduction

Neurodevelopmental disorders, including autism spectrum disorder, have complex polygenic etiologies. Affected individuals present with a spectrum of neurodevelopmental phenotypes, including autism, attention-deficit hyperactivity disorder, and speech and motor deficits. Our findings formalize a link between the synaptic protein AIDA-1 and a rare, previously undefined genetic disease we term ANKS1B haploinsufficiency syndrome. Neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and communication and motor disorders, have complex polygenic etiologies. These disorders are highly comorbid and share hereditary risk factors, suggesting that perturbations in pathways regulating brain development can result in a range of neurodevelopmental phenotypes[1]. We describe monogenic CNVs in ANKS1B in individuals that display a spectrum of neurodevelopmental phenotypes, including ASD, ADHD, and speech and motor deficits. Along with new evidence that AIDA-1 interacts with multiple regulators of neural development, our findings demonstrate that haploinsufficiency of ANKS1B leads to a previously uncharacterized neurodevelopmental syndrome

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Conclusion