Table 2 Genes linked to NDs identified through genotype-first approaches

ADNP

20q13.13

ASD, ID, loss of expressive language, facial dysmorphisms

[17]

AHDC1

1p35.3

ID/DD, hypotonia, mild dysmorphic facial features, sleep apnea

[59]

ANKRD11

16q24.3

KGB syndrome: macrodontia of central upper incisors, dental anomalies, facial dysmorphism, ASD, hyperactivity, hearing loss, heart defects

[60, 61]

ARID1A

1p36.11

Coffin–Siris syndrome with sucking/feeding difficulties, distinct faces including some facial coarseness with short nose, gastrointestinal complications, some hearing and visual impairments, prone to infection, hypotonia, structural CNS abnormalities, mild to severe ID/DD, behavioral abnormalities

[62, 63]

ARID1B

6q25.3

Highly variable Coffin–Siris syndrome with hypoplasia of the corpus callosum, hearing problems

[62, 64]

ARID2

12q12

ID/DD, ADHD, short stature, dysmorphic facial features, Wormian bones

[65]

AUTS2

7q11.22

ID, ASD, short stature, microcephaly, cerebral palsy, facial dysmorphism

[66]

BRWD3

Xq21.1

Mild to moderate ID, speech delay, behavioral disturbances, macrocephaly, dysmorphic facial features, skeletal symptoms

[67]

CHAMP1

13q34

ID, speech impairment, motor DD, muscular hypotonia, dysmorphic features

[68]

CHD2

15q26.1

Archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences, ID, ± ASD

[38, 69–71]

CHD8

14q11.2

ASD, macrocephaly, distinct faces, gastrointestinal complaint, sleep disturbance

[16]

CTNNB1

3p22.1

ID, microcephaly, limited speech and progressive spasticity

[72, 73]

CUL4B

Xq24

X-linked ID, cerebral malformations, seizures, tremors, gait abnormalities, behavioral problems, macrocephaly, short stature, obesity, hypogonadotropic hypogonadism, variable dysmorphic features

[74]

DDX3X

Xp11.4

ID, hypotonia, movements disorders, behavior problems, corpus callosum hypoplasia, EP

[53]

DEAF1

11p15.5

Severe ID, severely affected speech development, behavioral problems

[75]

DYNC1H1

14q32.31

Severe ID, neuronal migration defects, broad phenotypic spectrum

[76]

DYRK1A

21q22.13

DD, ASD, microcephaly, late-onset EP, severe anxiety

[18]

GATAD2B

1q21.3

Severe ID, childhood hypotonia, limited speech, tubular nose with broad nasal tip, short philtrum, sparse hair and strabismus

[77]

GRIN2A

16p13.2

Epilepsy–aphasia spectrum disorders

[78]

HDAC8

Xq13.1

ID, behavioral problems (including ASD in some patients), delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, broad nose and dental anomalies

[79]

HIVEP2

6q24.2

ID, structural brain anomalies, hypotonia, mild dysmorphic features

[80]

KCNH1

1q32.2

Severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail aplasia or hypoplasia, proximal implanted and long thumb and long great toes

[81]

KCNT1

9q34.3

Highly pleiotropic, including nocturnal frontal lobe EP, malignant migrating focal seizures of infancy, Ohtahara syndrome, multifocal EP, cardiac disturbances

[82]

KDM5C

Xp11.22

X-linked ID

[83]

KIAA2022

Xq13.3

X-linked ID, ASD features, strabismus

[84]

KIF1A

2q37.3

Cognitive impairment, variable cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, EP

[85]

KIF4A

Xq13.1

ID, EP

[86]

KIF5C

2q23.1

Severe ID, EP, microcephaly, cortical malformation

[86]

MAN1B1

9q34.3

ID, delayed motor and speech development, obesity, macrocephaly

[87]

MLL2 (KMT2D)

12q13.12

Severe form of Kabuki syndrome with distinct facial features (large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, flat nasal tip with a broad nasal root, a thin upper lip and a full lower lip)

[88]

MYT1L

2p25.3

Syndromic ID and/or central obesity

[89]

NRXN1

2p16.3

Predisposition for idiopathic generalized EP syndromes

[90]

PGAP1

2q33.1

ID, cerebral visual impairment

[91]

PHF21A

11p11.2

Potocki–Shaffer syndrome associated with ID and craniofacial anomalies

[92]

PPP2R1A

19q13.41

ID, hypotonia, EP, frontal bossing, mild hypertelorism, downslanting palpebral fissures

[93]

PPP2R5D

6p21.1

ID, ASD, macrocephaly, hypotonia, seizures, dysmorphic features

[93, 94]

SCN1A

2q24.3

EP with febrile seizures plus generalized epilepsy with febrile seizure plus (GEFS+), epilepsy–aphasia

[38]

SCN2A

2q24.3

ID/DD, seizure disorders (epileptic encephalopathy); previously implicated in ASD and SZ

[38, 95, 96]

SCN8A

12q13.13

Early-infantile epileptic encephalopathy type 13, ± ID, hypotonia, movement disorders

[38, 97, 98]

SETBP1

18q12.3

ID, loss of expression language

[99]

SETD5

3p25.3

ID, facial dysmorphism

[100]

SLC6A1

3p25.3

Spontaneous spike-wave discharges associated with epileptic encephalopathy

[101]

SMARCA4

19p13.2

Coffin–Siris syndrome with moderately coarse craniofacial features and behavioral abnormalities

[62, 63]

SMARCB1

22q11.23

Coffin–Siris syndrome with severe neurodevelopmental deficiencies, including severe ID, seizures, CNS structural abnormalities, no expressive words, scoliosis

[62, 63]

SMARCE1

17q21.2

Coffin–Siris syndrome with severe to moderate ID and a wide spectrum of manifestations

[63]

SMC3

10q25.2

Cornelia de Lange syndrome with postnatal microcephaly, moderately distinctive craniofacial appearance, mild prenatal growth retardation that worsens in childhood, some congenital heart defects, absence of limb deficiencies

[102]

SRCAP

16p11.2

Floating–Harbor syndrome: short stature with delayed bone age, deficits in expressive language, distinctive faces

[103]

SYNGAP1

6p21.32

Multiple seizure types, early DD, regression, ID

[38]

USP9X

Xp11.4

X-linked ID

[104]

WAC

10p11.23

ID/DD, hypotonia, behavioral problems, eye abnormalities, constipation, feeding difficulties, seizures, sleep problems, dysmorphic features

[105]

ZMYND11

10p15.3

ID, ASD, aggression, complex neuropsychiatric features

[99]