Siderius X-Linked Mental Retardation Syndrome

A number sign (#) is used with this entry because of evidence that Siderius-type X-linked syndromic mental retardation (MRXSSD) is caused by mutation in the PHF8 gene (300560) on chromosome Xp11.

Clinical Features

Siderius et al. (1999) described a family with 3 males (the propositus and his maternal uncle and cousin) with mild to borderline mental retardation. All 3 had similar facial features, with a long face and a broad nasal tip. Two of the cases had cleft lip and palate, and 1 had preaxial polydactyly and cryptorchidism. Results of cytogenetic analysis and molecular studies for fragile X syndrome (300624) were normal.

Laumonnier et al. (2005) reported a family with males who had mental retardation and clinical features similar to those in the family reported by Siderius et al. (1999). The proband was a 25-year-old male with mental retardation, a repaired cleft lip, a long face with broad nasal tip, long hands with long thin fingers, and flat feet with long thin toes. He had 2 maternal uncles who had died in infancy and reportedly had bilateral cleft lip and palate; a third maternal uncle, who had died in a car accident, had mild mental retardation without clefting.

Mapping

By linkage analysis in a family with mental retardation and cleft lip and palate, Siderius et al. (1999) obtained a maximum lod score of 2.78 (theta = 0.0) for the DXS441 locus with flanking markers DXS337 and DXS990, defining the region Xp11.3-q21.3.

Cytogenetics

Qiao et al. (2008) reported 2 brothers with autism spectrum disorder (209850), intellectual disability, and facial dysmorphism associated with a maternally inherited 470-kb interstitial microdeletion on chromosome Xp11.22, encompassing all of the PHF8 and FAM120C (300741) genes and part of the WNK3 gene (300358). Somatic features included cleft lip and palate, hypertelorism, asymmetric coarse facies, low-set dysplastic ears, widened nasal root and bridge, notched nasal tip, conductive and/or sensorineural hearing loss, long fingers, and broad halluces. The carrier mother showed 100% skewed X inactivation of the aberrant chromosome. Population screening of 481 patients with autism spectrum disorder and 282 control X chromosomes did not identify additional subjects carrying this deletion.

Pathogenesis

Loenarz et al. (2010) reported that recombinant PHF8 is an Fe(II) and 2-oxoglutarate-dependent N-epsilon-methyl lysine demethylase, which acts on histone substrates. PHF8 is selective in vitro for N-epsilon-di- and monomethylated lysine residues and does not accept trimethyl substrates. Clinically observed mutations to the PHF8 gene cluster in exons encoding for the double-stranded beta-helix fold and are expected to disrupt catalytic activity. The PHF8 F279S mutation (300560.0004), which is associated with mild MR, mild dysmorphic features, and cleft lip and palate, modifies a conserved hydrophobic region, rendering the enzyme catalytically inactive. Loenarz et al. (2010) hypothesized that dependence of PHF8 activity on oxygen availability may explain an association between maternal hypoxia and facial clefting.

Molecular Genetics

In the 3 affected males from the family reported by Siderius et al. (1999) and in a 25-year-old male with mental retardation and similar clinical features, Laumonnier et al. (2005) identified a deletion (300560.0001) and a nonsense mutation (300560.0002) in the PHF8 gene, respectively. Obligate female carriers in both families were found to be heterozygous for the mutations.

In a male with mental retardation, microcephaly, and cleft lip and palate, Abidi et al. (2007) identified a de novo mutation in the PHF8 gene (300560.0003).

In 2 Finnish brothers with X-linked mental retardation and cleft lip/cleft palate, Koivisto et al. (2007) identified a mutation in the PHF8 gene (300560.0004). Their unaffected mother was a carrier. The patients had mild facial dysmorphic features, including backward sloping foreheads and prominent supraorbital ridges. Several deceased male family members were reportedly affected.