TABLE 1.

A summary of clinical and molecular features of inverse brain growth phenotype due to variants in CCND2, AKT3, PTEN, NSD1, MYCN, EZH2, and MIR17HG

Gene	Megalencephaly/macrocephaly Disease (OMIM)	Protein function	Clinical features	Inheritance	Type of variants	Microcephaly Disease (OMIM)	Protein function	Clinical features	Inheritance	Type of variants
CCND2	MPPH3 (#615938)	Gain	Megalencephaly, postaxial polydactyly, hypotonia, epilepsy, intellectual disability, oromotor dysfunction, polymicrogyria	De novo/AD	Missense, nonsense	Microcephaly	Lossa	Microcephaly, symmetric short stature, hypotonia, mild intellectual disability, mild motor delay	De novo/AD	Missense, small indels
AKT3	MPPH2 (#615937)	Gain	Megalencephaly, polymicrogyria/cortical dysplasia, postaxial polydactyly, hypotonia, epilepsy, intellectual disability, oromotor dysfunction, connective tissue laxity, vascular malformations	De novo/AD	Missense, duplication	Postnatal microcephaly	Haploin sufficiency/loss	Microcephaly, callosal abnormalities, seizures, hypotonia, dysmorphic features	De novo/AD	Microdeletion 1q43-q44
PTEN	Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS); Lhermitte-Duclos disease (LDD); (#158350)	Loss	Megalencephaly, facial trichilemmomas, acral keratoses, papillomatous papules, hamartoma, increased risk for breast, thyroid, and endometrial carcinoma; hamartomatous polyps of the gastrointestinal tract, mucocutaneous lesions, developmental delay, lipomas, hemangiomas	De novo/AD	Missense, nonsense, small/large deletions	Microcephaly	Gain	Primary microcephaly, autism spectrum disorder, intellectual disability	AD	Microduplication 10q23.31
	Autism spectrum disorder with macrocephaly (#605309)	Loss	Megalencephaly, abnormal facial features, and delayed psychomotor development resulting in autistic behavior or mental retardation	De novo/AD	Missense, nonsense, small/large deletions
NSD1	Sotos syndrome (#117550)	Loss	Megalencephaly, somatic overgrowth, dysmorhpic facial features, cardiac issues, skeletal issues, renal anomalies, developmental delay/intellectual disability	De novo/AD	Missenese, nonsense, splicing defects, frameshift, deletions	Microcephaly	Gain	Microcephaly, short stature, seizures, developmental delay/intellectual disability, dysmorphic facial features	De novo/AD	Microduplication 5q35
MYCN	MYCN related megalencephaly syndrome	Gain	Brain abnormalities (megalencephaly, ventriculomegaly, hypoplastic corpus callosum); Intellectual disability, polydactyly; neuroblastoma	De novo	Missense (c.173C>T)	Feingold syndrome type 1 (#164280)	Loss	Microcephaly; Limb abnormalities (clinodactyly, syndactyly, thumb hypoplasia); Esophageal and or duodenal atresia; Learning disabilities; Characteristic facial features (micrognathia, short palpebral fissures)	AD/unknown de novo	Nonsense, missense, large deletions, partial and entire gene deletions
EZH2	Weaver syndrome (#277590)	Loss	Megalencephaly, overgrowth, distinctive facial gestalt, accelerated bone maturation, developmental delays	De novo	Missense	Microcephaly and developmental delays	Gain	Growth failure, hypotonia, “clover-leaf” shaped skull, large anterior fontanelle, sparse eyebrows, upslanting palpebral fissures, and small ears, developmental delays	De novo	Missense
MIR17HG	MIR17HG related overgrowth syndrome	Gain	Megalencephaly, developmental delay, skeletal and digital abnormalities, tall stature	De novo	13q31.3 microduplications	Feingold syndrome type 2 (#614326)	Loss	Microcephaly, brachymesophalangy, toe syndactyly, short stature, cardiac anomalies, growth hormone deficiency, aortic dilation, phalangeal joint contractures, memory, and sleep problems	De novo	13q31.3 microdeletions

Notes: When available, the OMIM number is listed, otherwise the disorder has not yet been described in OMIM.

Abbreviations: AD, autosomal dominant; IUGR, intrauterine growth restriction; MPPH, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; UK, unknown.

^aPredicted loss of function due to premature stop codon based on the five cases reported here.