Epigenetic regulation of autophagy-related genes: Implications for neurodevelopmental disorders

Figures & data

Figure 1. Different levels of autophagy regulation and its’ effect on neuronal development and function.

Figure 2. Overview of how the different epigenetic modifiers regulate autophagy and the associated NDDs.

Table 1. Chromatinopathy causing genes associated with altered autophagy regulation and the respective clinical phenotypes.

Gene	Autophagy switch	Associated disorder	Clinical phenotype *(overlap with common symptoms of congenital disorders of autophagy)
Histone modifiers
EZH2	OFF	ASD Weaver syndrome (OMIM # 277590)	Tall stature, mild to moderate ID*, developmental delay*, macrocephaly, characteristic facial appearance*, mild to severe scoliosis, hypo-/hypertonia*, poor coordination
SETD2	ON	Luscan-Lumish syndrome (OMIM # 616831)	Macrocephaly, speech delay, ID*, ASD*, distinctive facial appearance, postnatal overgrowth, epileptic seizures*
KAT8	ON	Syndromic ID Li-Ghorbani-Weisz-Hubshman syndrome (OMIM # 618974)	Global developmental delay*, mild to moderately ID*, language delay, mild dysmorphic features*, epilepsy*, and structural brain abnormalities* (e.g. enlarged ventricles, thin corpus callosum, and gray matter nodular heterotopia)
KANSL1	ON	Koolen-de Vries syndrome (OMIM # 610443)	Hypotonia*, developmental (speech) delay*, mild to moderate ID*, epileptic seizures*, dysmorphic facial features, structural brain abnormalities* (e.g. corpus callosum hypoplasia/aplasia, enlarged ventricles, hydrocephalus, and/or heterotopias), congenital heart, renal, urologic anomalies, musculoskeletal problems (e.g. scoliosis, short stature), a friendly/amiable disposition
KDM6A	ON	Kabuki syndrome 2 (OMIM # 300867)	Mild to moderate ID*, hypotonia*, congenital heart anomalies, short stature, skeletal anomalies, characteristic facial features*
KDM6B	ON	NDD with coarse facies and mild distal skeletal abnormalities (OMIM # 618505)	Developmental delay*, poor speech acquisition, hypotonia, variable behavioral abnormalities* (e.g. ASD, hyperactivity, ADHD), coarse facial features*
PHF8	ON	PHF8-XLID (OMIM # 300263)	Developmental delay*, mild to borderline ID*, learning difficulties, craniofacial dysmorphology* (cleft lip/palate)
SETD1A	ON(?)	NDD with speech impairment and dysmorphic facies (OMIM # 619056)	Schizophrenia, global developmental delay*, and/or ID*, speech impairment, behavioral and psychiatric problems, subtle facial dysmorphisms*
KMT2A	ON(?)	Wiedemann-Steiner syndrome (OMIM # 605130)	Developmental delay*, mild to moderate ID*, hypotonia*, behavioral problems (ASD*, anxiety features), short stature, facial dysmorphism*, growth hormone and immune deficiency, hypertrichosis
KDM3B	ON	Diets-Jongmans syndrome (OMIM # 618846)	Mild to moderate ID*, distinctive facial dysmorphisms*, behavioral problems (e.g. ADHD, ASD*) short stature, epilepsy*, hearing loss, childhood hypotonia*
EHMT1	OFF	Kleefstra syndrome (OMIM # 610253)	ID*, childhood hypotonia*, severe expressive speech delay, ASD*, characteristic facial features, congenital heart malformations, renal defects, epilepsy*, recurrent infections, behavioral problems (abrupt behavioral changes around adolescence, e.g., regression, bipolar mood disorder, autistic features)
KDM1A	OFF	Cleft palate, psychomotor retardation, and distinctive facial features (OMIM # 616728)	ID*, developmental and speech delay*, cleft palate*, hypotonia*, various structural brain abnormalities*
DNA methyltransferases
DNMT3A	OFF	Tatton-Brown-Rahman syndrome (OMIM # 615879) Heyn-Sproul-Jackson syndrome (OMIM # 618724)	Mild to moderate ID*, overgrowth, macrocephaly*, distinctive facial appearance*, hypotonia, seizures*, scoliosis, hypotonia*, increased susceptibility to the development of acute myeloid leukemia Microcephaly*, short stature, impaired intellectual development*
MECP2	OFF	Rett syndrome (OMIM # 312750)	Developmental stagnation at 6–18 months of age followed by regression of acquired skills, loss of speech, jerky truncal ataxia*, autism, ‘acquired’ microcephaly*, seizures*, and mental retardation
Chromatin remodelers
CHD6	ON	Hallermann-Streiff syndrome (OMIM # 234100)	Short stature, hypotrichosis, characteristic facial features*, mental retardation*
CHD2	ON(?)	Developmental and epileptic encephalopathy (OMIM # 615369)	Epilepsy*, developmental delay*, cognitive regression, ID*, ASD*
Transcription factors
ADNP	ON	Helsmoortel-Van Der Aa syndrome (OMIM # 615873)	Developmental delay*, behavioral problems (e.g. ASD, ADHD, obsessive compulsive behavior)*, facial dysmorphisms*, ID*, hypotonia*, congenital heart defects, short stature, dysmorphic features, seizures*, recurrent infections
YY1	ON	Gabriele-de Vries syndrome (OMIM #617557)	Delayed psychomotor development, ID*, speech delay, behavioral problems*, abnormal movement, dysmorphic facial features*, brain abnormalities* (e.g. enlarged ventricles, white matter abnormalities).
YY1AP1	ON	Grange syndrome (OMIM #602531)	Early-onset vascular disease, learning disabilities*
Cytoplasmic protein modifiers
EP300	OFF	Rubinstein-Taybi syndrome 2 (OMIM #613684)	Mental retardation*, postnatal growth deficiency, microcephaly*, dysmorphic facial features*
EHMT1	ON	See above	See above
SETD2	OFF	See above	See above