Table 3.

Key characteristics of intellectual disability genes that have been inferred as subject to recent positive selection in the human lineage

Gene	Phenotypic effects	Developmental-genetic functions
Genes in Rho-GTPase pathway
FGD1	Mutations cause Aarskog-Scott syndrome (FacioGenital Dysplasia), which involves macrocephaly and genital anomalies (Schwartz et al. 2000; Orrico et al. 2004; Bottani et al. 2007)	FGD1 gene product acts as upstream effector of Rho GTP-ases, and is involved in neurite outgrowth and dendritic spine development (van Galen and Ramakers 2005)
FMR1	Mutations cause Fragile X syndrome, which involves macrocephaly, macroorchidism (large testis), reduced cerebellar vermis, and a high incidence of autism (Terracciano et al. 2005; Belmonte and Bourgeron 2006)	FMR1 gene product, FMRP, interacts with CYFIP1,2, which mediate Rho GTPase activation (Billuart and Chelly 2003); mental retardation involves altered glutamatergic signaling, and immature dendritic spines (van Galen and Ramakers 2005)
OPHN1	Mutations involve cerebellar hypoplasia, hypogonadism, and macrocephaly in a notable proportion of cases (Chiurazzi et al. 2004; Chabrol et al. 2005; Kleefstra and Hamel 2005;Zanni et al. 2005)	OPHN1 gene product regulates RhoA activity, affects glutamatergic signaling; mouse mutants show immature dendritic spines (Govek et al. 2005;Chabrol et al. 2005; Zanni et al. 2005; Khelfaoui et al. 2007)
Genes in DNA repair pathways
FANCA & FANCC	Mutations cause Fanconi Anemia, an autosomal recessive condition that involves microcephaly, growth retardation, bone marrow failure, skeletal malformations and increased cancer risk (Gennery et al. 2004; Wang 2007)	FANC genes maintain genomic stability and are required for neural stem cell maintenance in brain development; aging of stem cell pools may underlie Fanconi Anemia phenotypes (Sii-Felice et al. 2008)
NBS1	Mutations cause Nijmegen Breakage syndrome, an autosomal recessive condition characterized by microcephaly, immunodeficiency, increased cancer risk, and growth retardation (Gennery et al. 2004; Demuth and Digweed 2007; O'Driscoll et al. 2007)	NBS1 gene product maintains genomic stability via repair of double-stranded DNA breaks, and helps to maintain telomeres (Matsuura et al. 2004; Zhang et al. 2006b); interacts closely with ATM gene product in DNA damage response pathway (Difilippantonio and Nussenzweig 2007)
ERCC8	Mutations are one cause of Cockayne syndrome, an autosomal recessive condition involving microcephaly, growth retardation, hypogonadism, and symptoms of premature aging (Rapin et al. 2006; Niedernhofer 2008)	ERCC8 gene product functions in repair of damage in actively-transcribed genes (Lainé and Egly 2006) and repair of oxidative DNA damage (D'Errico et al. 2007)