Table 1.

Curated list of confirmed or putative dose-sensitive genes mediating intellectual disability

Gene	Role	Loss-of-function syndrome	Overexpression-related abnormality or syndrome		Human Ensembl transcript numbera
			Monogenic mouse model	Clinical polygenic syndrome
MECP2 b	Transcription	Rett syndrome	Yes	Yes	ENST00000303391.6
TCF4 c	Transcription	Pitt-Hopkins	Yes	Yes	ENST00000354452.3
MEF2C d	Transcription	MEF2C Haploinsufficiency	Noe (Drosophila data available)	Yes	ENST00000340208.5
NSD1 f	Transcription	Sotos	Nog (Drosophila data available)	Yes	ENST00000439151.2
ATRX h	Transcription	ATRX	Yes	Yes	ENST00000373344.5
MBD5 i	Transcription	MAND	Noj (Drosophila data available)	Yes	ENST00000407073.1
ZEB2 k	Transcription	Mowat-Wilson	Nol (Drosophila data available)	Yes	ENST00000558170.2
UBE3A m	Degradation and transcription	Angelman	Yes	Yes	ENST00000232165.3
DYRK1A n	Phosphorylation	DYRK1A	Yes	Yes	ENST00000339659.4
RPS6KA3 o	Phosphorylation	Coffin-Lowry	Nop (Drosophila data available)	Yes	ENST00000379565.3
SLC6A1 q	Transporter	Doose	Yes	Yes	ENST00000287766.4

Inactivating mutations in the genes listed here have been shown to mediate neurodevelopmental disorders characterized by intellectual disability as well as other phenotypes, such as seizures, stereotypies, abnormal speech and/or abnormal head size. Although the exact age of onset varies across loss-of-function syndromes, many of these syndromes are evident by 2 years of age. Reciprocal (overexpression-related) disorders may be mediated wholly or in part by the same genes. The contribution of a specific gene to specific phenotypes associated with a human chromosomal duplication may not always be known. To be clear, patients with supernumerary protein expression typically have duplications spanning larger chromosomal regions that encompass, but are not limited to, the genes indicated in this table. Therefore, Table 1 includes monogenic duplication mouse models that underscore the potential dose-sensitivity of these genes. Clinical vignettes describing intragenic duplications (which may yield truncated protein) are not considered in this table.

^a3ʹ UTR sequences are accessible at www.targetscan.org. The Ensembl transcript numbers listed here were used for analyses.³²

^b MECP2 references.^{1,4,5,16–21,38}

^c TCF4 (transcription factor 4) references.^39–45

^d MEF2C (myocyte enhancer factor 2C) references.^46–49

^eOverexpression of the Drosophila orthologue MEF2 has been shown to cause lethality or abnormal wing morphology.⁴⁸

^f NSD1 (nuclear receptor binding SET domain protein 1) references.^50–53

^gOverexpression of the Drosophila orthologue NSD has been shown to cause development delay, early lethality, decreased wing size and disrupted organization of the eye (consequences of overexpression vary depending on the spatial extent of overexpression).⁵⁴

^h ATRX (alpha-thalassemia/mental retardation, X-linked) references.^55–58

ⁱ MBD5 (methyl-CpG binding domain protein 5) references.^59–62

^jOverexpression of the Drosophila orthologue sba has been shown to cause wing abnormalities.⁶¹

^k ZEB2 (zinc finger E-box binding homeobox 2) references.^48,63,64

^lOverexpression of the Drosophila orthologue ZFH1 causes lethality.⁴⁸

^m UBE3A (ubiquitin-protein ligase E3A) references.^65–72

ⁿ DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) references.^73–79

^o RPS6KA3 (ribosomal protein S6 kinase A3) references.^80–86

^pOverexpression of the Drosophila orthologue S6KII has been shown to exert a dominant negative effect in operant place learning.⁸⁶

^q SLC6A1 references.^87–90