Detailed clinical descriptions of the families with mental retardation–causing variants in six of the nine genes implicated in XLMR identified in this screen have been published (AP1S2, BRWD3, CUL4B, SLC9A6, UPF3B, ZDHHC9)16-21 and therefore their features are only reviewed briefly here. Mental retardation ranged from mild to severe and most families were previously classified as having nonsyndromic mental retardation. Following the identification of the genes involved in mental retardation, however, phenotypic characteristics common to some affected males were identified: for example, epilepsy and ataxia (SLC9A6), macrocephaly (BRWD3), relative macrocephaly, hypogonadism, central obesity and tremor (CUL4B), Marfanoid habitus (ZDHHC9), elements of the FG and Lujan-Fryns syndromes (UPF3B), epilepsy (SYP) and nystagmus (CASK). The encoded proteins have roles in vesicle trafficking (AP1S2), chromatin structure (BRWD3), nonsense-mediated RNA decay (UPF3B), ubiquitination (CUL4B), post-translational modification by palmitoylation (ZDHHC9), NA+/H+ exchange (SLC9A6), synaptic function (SYP) and synaptic signal transduction (CASK).
