Table 1.

Genetic neurodevelopmental disorders associated with abnormal postnatal brain growth.

Disorder	Clinical Description	Genetic Description	Postnatal Disruptions	References
Monogenic Postnatal Microcephalies
Angelman Syndrome (AS)	Characterized by severe intellectual disability, absent speech, seizures, postnatal microcephaly, movement disorder, developmental delay, and a behavioral profile that includes a happy demeanor and hyperactivity	Loss of expression of the maternally inherited allele of UBE3A	Decreased dendritic spine density and abnormal spine morphology, white matter pathology, and altered connectivity	[34]
Rett Syndrome (RTT)	Characterized by typical early development followed by regression, which involves loss of acquired skills and language, intellectual disability, gait abnormalities, stereotypic hand movements, postnatal microcephaly, and seizures (mainly affects females)	Loss-of-function mutations in the X-linked gene MECP2 (however, can be associated with mutations in CDKL5 and FOXG1)	Decreased dendritic growth and spine density, fewer spines, white matter pathology, and compromised glial function	[35,36,37*]
Christianson Syndrome (CS)	Characterized by severe intellectual disability, absent speech, ataxia, and epilepsy Frequently presents with postnatal microcephaly, craniofacial dysmorphology, eye movement abnormalities, progressive neurologic dysfunction, and loss of early acquired motor skills (mainly affects males)	Loss-of-function mutations in the X-linked gene SLC9A6	Decreased axonal and dendritic arborization, decreased spine density, and gray matter atrophy (most notable in cerebellum and brainstem)	[38–40]
Monogenic Postnatal Macrocephalies
PTEN Hamartoma Tumor Syndrome (PHTS)	Characterized by a predisposition of tumors Often associated with Lhermitte-Duclos disease, developmental disabilities, macrocephaly, and autism spectrum disorder (ASD)	Germline heterozygous loss-of-function mutations in PTEN	Excess glial population, hypertrophy of dendritic arborization, increased dendritic spine density, and white matter abnormalities	[41–42]
Tuberous Sclerosis Complex (TSC)	Multi-system disease commonly presenting with dermatological, renal, and neurological manifestations Neurological manifestations include epilepsy, cognitive disabilities, behavioral problems, autism, and macrocephaly	Heterozygous loss-of-function mutations in either TSC1 or TSC2	Astrogliosis, white matter abnormalities, structurally compromised axons, and altered structural connectivity Projection neurons within cortical tubers exhibit shortened dendrites, abnormal spine morphology, and decreased dendritic spine density	[43–46]
Neurodegenerative Disorders
Cockayne Syndrome	Neurodegenerative disorder characterized by severe motor and cognitive developmental delays, intellectual disability, microcephaly, multi- organ degeneration, progessive hearing loss, retinopathy, and sun sensitivity	Autosomal recessive mutations in ERCC6 (also known as CSB) or ERCC8 (also known as CSA)	Neurological manifestations include neuronal loss, gliosis, demyelination, and axonal degeneration	[47–49]
KIF1A-associated Neurodegenerative Syndrome	Neurodegenerative disorder characterized by severe developmental delay, hypotonia, microcephaly, cortical visual impairment, ataxia, epilepsy, and movement disorders	De novo (likely dominant-negative) mutations in KIF1A	Progressive brain atrophy and cerebral white matter reduction, likely caused by impaired axonal synaptic vesicle transport	[50*]
Complex Disorders
Autism Spectrum Disorder (ASD)	Genetically and clinically heterogeneous neurodevelopmental disorder characterized by impaired communication and social interactions, and stereotyped behaviors	Ongoing area of research, but examples include: PTEN mutations (associated with macrocephaly) DYRK1A mutations (associated with microcephaly) 16p11.2 (duplications associated with microcephaly and deletions with macrocephaly) 1q21.1 (deletions associated with microcephaly and duplications with macrocephaly)	Increased cortical thickness and spine density, decreased diffusion and resting state connectivity, and widespread reductions in white matter tract integrity (however, may be limited to right inferior longitudinal fasiculus after matching for head motion)	[51–53,54**,55– 59,60**,61*]
Schizophrenia	Criteria include positive symptoms (i.e., hallucinations, delusions, disorganized behavior) and negative symptoms (i.e., blunted affect, lack of motivation)	Ongoing area of research, but examples include: Altered expression of C4 genes (i.e., C4A and C4B)	Exaggerated parieto-frontal-temporal gray matter loss (predominantly in prefrontal and temporal cortices), reduced spine density and neuropil in deep layer III and layer V of prefrontal cortex, abnormal functional and structural connectivity, and altered white matter integrity	[62–64,65**]