A number sign (#) is used with this entry because of evidence that X-linked syndromic intellectual developmental disorder-33 (MRXS33) is caused by mutation in the TAF1 gene (313650) on chromosome Xq13.

X-linked syndromic intellectual developmental disorder-33 (MRXS33) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and characteristic facial features (summary by O'Rawe et al., 2015).

O'Rawe et al. (2015) reported 12 boys from 9 unrelated families with a complex X-linked neurodevelopmental syndrome. The boys had global developmental delay, intellectual disability with delayed speech and language, generalized hypotonia, and joint hypermobility. Most had intrauterine and/or postnatal growth retardation and oropharyngeal dysphagia. Common facial dysmorphic features included prominent supraorbital ridges, downslanting palpebral fissures, deep-set eyes, sagging cheeks, long philtrum, low-set and protruding ears, long face, high-arched palate, thin upper lip, pointed chin, and broad upturned nose with bulbous nasal tip. Other widely shared features included hearing impairment, microcephaly, and hypoplasia of the corpus callosum. Some additional neurologic features included spastic diplegia, dystonic movements, and tremors. Three patients from 1 family had seizures soon after birth, but other patients did not have seizures. Some had autistic behaviors. All patients also had a characteristic gluteal crease with a sacral caudal remnant, although spine imaging on 2 patients did not show any major underlying defect. Extensive clinical information was available in the supplemental material.

O'Rawe et al. (2015) reported 2 unrelated boys with delayed psychomotor development, intellectual disability, dysmorphic facial features, and severe neurodegenerative phenotype associated with small duplications (0.423 Mb and 0.42 Mb, respectively) of chromosome Xq13 encompassing the TAF1 gene and other genes. One of the deletions was inherited from an unaffected mother who showed skewed X-inactivation; this patient also had a deletion at chromosome 17q21. The deletion in the other patient occurred de novo.

In 12 boys from 9 unrelated families with MRXS33, O'Rawe et al. (2015) identified 9 different hemizygous mutations in the TAF1 gene (see, e.g., 313650.0002-313650.0006). Most of the mutations occurred de novo, although 3 were inherited from an unaffected mother, 1 of whom showed skewed X-inactivation. Functional studies were not performed, but many of the variants affected highly conserved residues in domains critical for interaction with TAF7 (600573) and were predicted to disrupt this interaction. Gene expression studies in 1 family with a missense mutation (I1337T; 313650.0002) suggested that the phenotype is associated with downregulation of a set of genes regulated by E-box proteins. The mutations were found by several strategies, including whole-genome sequencing, exome sequencing, targeted gene-panel sequencing, and microarray-based strategies, and all were confirmed by Sanger sequencing.

O'Rawe et al. (2015) found that knockdown of the taf1 gene in zebrafish resulted in a 10% reduction in the relative area of the optic tectum, suggesting a neuronal defect.