TABLE II. Examples of ASD-risk genes and their associated additional phenotypes. ADD, attention deficit disorder; ADHD, attention-deficit hyperactivity disorder; ASD, autism spectrum disorder; BAF, BRG1/BRM associated factor (also known as SWI/SNF); CASK, Calcium/calmodulindependent serine protein kinase; CHD, congenital heart disease; CNS, central nervous system; CPVT, catecholaminergic polymorphic ventricular tachycardia; CSS1, Coffin-Siris syndrome 1; DD, developmental delay; GI, gastrointestinal; GU, genitourinary abnormality; het, heterozygous; HVDAS, Helsmoortel-Van der Aa syndrome; ID, intellectual disability; IUGR, intrauterine growth retardation; LD, learning disability; mod-severe ID, moderate-to-severe intellectual disability; MRI, magnetic resonance imaging; NMDAR, N-methyl-Daspartate receptor; OMIM, Online Mendelian Inheritance in Man database; PSD, postsynaptic density; SCZ, schizophrenia; SD, standard deviation; SWI/SNF-A, a chromatin remodeling complex.^A SWI/SNF complex in yeast.^B Initial ADNP mutations were identified by screening ASD cohorts.^C Reports are rare.^D ANK2 mutations have been identified in multiple large ASD cohorts with little accompanying phenotypic information.^E 16/35 (45.7%) had ASD.¹¹⁹ .

ASD-risk gene	Chromosomal location/ gene name and function	ASD penetrance	Other neurobehavioral phenotypes	Dysmorphology	Other somatic abnormalities	References
Chromatin remodeling
CHD8	14q11.2, Chromodomain helicase DNA binding protein 8. Master transcriptional repressor	With truncating mutations, possibly complete	ID	Truncating mutations - common facial dysmorphism: prominent supraorbital ridges, hypertelorism, pointed chin	GI dysmotility, possible increased malignancy risk	19
ADNP	20q13.13, Activity-dependent neuroprotective protein. Presumed transcription factor. Cterminus interacts with 3 essential components of BAF complex,A which regulates gene expression by mediating chromatin remodeling	Complete: causes Helsmoortel- Van der Aa syndrome (HVDAS, OMIM ≠615873), which belongs to the group of SWI/SNFrelated ID disordersB	Other features of HVDAS: ID, hypotonia, seizures, ADHD/ ADD, anxiety disorders	Dysmorphology variable. Common features: prominent forehead, high hairline, broad nasal bridge, thin upper lip, long/ smooth philtrum, polydactyly	Feeding problems, CHD, brain MRI abnormalities	11,97
ARID1B	6q25.3, AT-rich interactive domain-containing protein 1B. Largest subunit of the mammalian SWI/SNF-A chromatin remodeling complex	Incomplete	AD mutations associated with: SWI/SNF ID syndrome Coffin- Siris syndrome (CSS1, OMIM≠ 135900), apparently nonsyndromic ID, syndromic short stature	Features in some CCS1 patients: hypertrichosis, coarse facies, malformed ears, short stature, small, hypoplastic 5th fingers. Clinical data on phenotypes of apparently nonsyndromic ID/ASD patients is lacking	Documented in CSS1: brain MRI abnormalities (especially agenesis of the corpus callosum), cryptorchidism in males, palatal abnormalities	98-100
TBR1	2q24.2, T-box, brain 1. Coactivated by cask to induce transcription of T-element containing genes, including Reelin, which is essential for cerebrocortical development	Unknown	ID	Unknown - none reported	Growth retardation	22,101
Synaptic and cytoskeletal proteins
NRXN1 - het missense & truncating variantsC	2p16.3, Neurexin 1. Cell surface receptor that binds neuroligins to form a complex at CNS synapses	Incomplete	ADHD, LD, ID, SCZ	Mild facial dysmorphism in some (no other details)	Unknown - none reported	89,92,93,102
NRXN1 - deletions (limited to NRXN1 exons)	2p16.3, Neurexin 1. Cell surface receptor that binds neuroligins to form a complex at CNS synapses	20 %	DD, ID, hypotonia, bipolar disorder, ADHD, epilepsy, SCZ	Variably dysmorphic or nondysmorphic	Nonspecific brain MRI abnormalities, ocular abnormalities, other congenital anomalies	91,103,104
SHANK3	22q13.33, SH3 and multiple Ankyrin repeat domain 3. Structural protein of the post-synaptic density (PSD). PSD is responsible for alignment of postsynaptic membrane proteins	Incomplete; penetrance for de novo truncating mutations is high, and most cases also have mod-severe ID	SCZ, ID, epilepsy, speech delay, ADHD/ ADD, hypotonia	Variable facial dysmorphism in some cases similar to Phelan- McDermid syndrome (del22q13.3 syndrome, Table I); some cases nondysmorphic; macrocephaly; large stature	None reported	105-107
SYNGAP1	6p21.3, Synaptic RASGTPase activating protein 1. Part of the N-methyl-d-aspartate receptor (NMDAR) complex located in the PSD of glutamatergic neurons	Incomplete (50%108)	Nonsyndromic ID [MRD5 OMIM≠ 612621]. Appears to be highly penetrant for ID and generalized epilepsy. Other findings: hypotonia, ataxia	Unknown - none reported	Acquired microcephaly. Brain MRI normal or nonspecific features	108-110
ANK2	4q25-q26, Ankyrin 2. Localizes membrane ion channels and transporters	UnknownD	Unknown	None reported	Associated with several cardiac arrhythmia syndromes, including long QT syndrome type 4 & CPVT	22,111
SCN2A	2q24.3, Sodium channel, voltage gated, type II alpha subunit. A subunit of a sodium channel	Incomplete	Spectrum of seizure disorders (benign familial neonatal seizures, infantile epileptic encephalopathy, neonatal seizures with later-onset episodic ataxia), SCZ, ID, brain MRI abnormalities	None reported	Optic atrophy, microcephaly	56,112-116
DYRK1A. Dualspecificity tyrosine phosphorylationregulated kinase 1A.	21q22.13 (located within the Down syndrome critical region). Protein kinase essential for neurogenesis, neuronal differentiation, synaptic plasticity	IncompleteE	ID, severe speech delay/absent speech, epilepsy, ataxia/ broad-based gait	An Angelman-like syndrome with distinct facial features: sparse scalp hair, deep-set eyes, hooded eyelids, prominent nasal root, pointed nasal tip, short chin (not reminiscent of Down syndrome)	IUGR, congenital microcephaly (—2 SD to —5 SD), brain MRI abnormalities (hypomyelination), eye defects, joint contractures, CHD, GU	117-119