X-linked Intellectual Disability via the TAF1 Gene

TAF1-associated X-linked intellectual disability (syndromic XLID type 33) is characterized by global developmental delay, and in particular a delay in the development of speech and language abilities. This disorder primarily affects males, however several affected females have also been documented in the literature. The most common features of the disorder, observed in over half of the affected individuals, include intellectual disability (64%), hypotonia (70%), speech and language delay (92%), gross motor delay (67%), and feeding difficulties (63%). Other commonly observed phenotypes include pre and post-natal growth retardation, short stature, microcephaly, seizures, brain abnormalities including hypoplasia of the corpus callosum and ventriculomegaly, sensorineural hearing impairment, gait disturbance, gastroesophageal reflux, sacral dimple, cryptorchidism, and congenital heart defects. More rarely observed in this syndrome are skeletal abnormalities including missing ribs, digit abnormalities, hip dysplasia, kyphosis and scoliosis, pectus abnormalities, joint hypermobility, pes planus, hypospadias, and mixed hearing loss. Behavioral abnormalities including autistic traits, recurrent hand-flapping, and self-injurious behavior are also observed in a minority of individuals. Patients do not have a recognizable facial gestalt, yet common facial characteristics include hypertelorism, deeply-set eyes, strabismus, wide nasal bridge, bulbous nose, anteverted nares, long philtrum, thin upper lip vermilion, retrognathia, flat occiput, and high palate. Onset of TAF1-intellectual disability can be observed prenatally with intrauterine growth retardation, brain malformations, or congenital heart defects, however, the primary features manifest postnatally. Affected females often carry de novo variants, and evidence suggests that female phenotype can vary due to skewed X-inactivation patterns, possibly even acting in a tissue-specific manner (O'Rawe et al. 2015. PubMed ID: 26637982; Cheng et al. 2019. PubMed ID: 31646703). 

TAF1 intellectual disability has been described in over 40 families, making it one of the more common causes of X-linked intellectual disability. While there is no treatment for this disorder, advantages of testing may include prognostic information, early identification and treatment of symptoms such as feeding difficulties, seizures, and hearing loss, and ability to join TAF1 family support groups, such as the "Amazing TAF1 Families" group on Facebook. For families with inherited causative variants, prenatal testing or pre-implantation genetic diagnosis may be implemented for future pregnancies. Alternatively, a confirmed de novo variant (implicating lower recurrence risk), may ease anxiety for reproductive planning. Additional testing for X-inactivation skewing may also be warranted for female carriers of TAF1 variants (see additional information on X-inactivation skewing in the genetics section).

Literature evidence primarily supports an X-linked recessive inheritance pattern for TAF1-XLID. Affected males can have hemizygous de novo variants, or inherit a pathogenic variant from an unaffected or mildly affected mother. Most affected females carry de novo variants, and where testing has been done, X-inactivation (XI) in affected females is highly skewed toward the normal allele. In addition, X-inactivation studies of unaffected females also usually shows a high degree of skewing. Therefore, X-inactivation skewing studies may be helpful when assessing the significance of a TAF1 variant during family segregation studies. The current XI studies also suggest that an as-yet unidentified X-linked dominant and possibly milder form of the disorder may also exist in females with pathogenic variants and a random pattern of X-chromosome inactivation (O'Rawe et al. 2015. PubMed ID: 26637982; Cheng et al. 2019. PubMed ID: 31646703).

The majority of pathogenic TAF1 variants are missense alterations, which are widely spread throughout the gene. Some enrichment of pathogenic variation is seen in the protein's four functional domains, particularly the large triple barrel-winged helix-α-helical domain, and the tandem bromodomain. However, many pathogenic variants also exist outside of these domains, supporting the critical nature of other TAF1 regions with no currently known function (Cheng et al. 2019. PubMed ID: 31646703). Other variant types exist in very small numbers, including synonymous alterations shown by functional studies to alter splicing and lead to early protein termination (O'Rawe et al. 2015. PubMed ID: 26637982). Large multi-gene duplications involving TAF1 have also been identified in patients with numerous overlapping features, however the identified duplications also contain several other genes known to be involved in neurodevelopment, therefore the contribution of TAF1 to the overall phenotype of these patients is not clearly elucidated (O'Rawe et al. 2015. PubMed ID: 26637982). Notably, frameshift and nonsense variants are extremely rare in the literature and public databases, suggesting that a majority of TAF1 loss of function alterations may be lethal (gnomAD).

TAF1 is located at Xq13.1, consists of 38 exons, and codes for a 1873 amino acid protein (NM_004606). TAF1 encodes the transcription initiation factor TFIID subunit 1, which is the largest subunit of the transcription factor TFIID complex. This complex is required for initiation of transcription of the majority of protein coding genes, via RNA polymerase II. Three different splice isoforms of this gene are known to be expressed, but they vary only minimally, with an additional or one fewer exon near the end of the protein (UniProt; Ensembl). A zebrafish TAF1 knockout model was lethal during embryonic development, demonstrating this gene's critical role in embryogenesis. Prior to death, embryos showed phenotypes consistent with neurodevelopmental abnormalities. Expression studies in mice have also shown high ubiquitous expression during embryonic development, followed by downregulation at later stages (Gudmundsson et al. 2019. PubMed ID: 31341187).

It is important to note that this test does not cover the TAF1 intronic insertions associated with X-linked dystonia-Parkinsonism, a common cause of torsion dystonia on the island of Panay in the Philipines (Bragg et al. 2017. PubMed ID: 29229810). PreventionGenetics does not currently offer a test for X-linked Dystonia-Parkinsonism, also known as DYT3. 

Pathogenic variants in TAF1 are expected to account for <0.1% of cases of intellectual disability (ID), and less than 1% of individuals with X-linked ID (XLID). In this context, it is important to note that pathogenic variants in over 140 genes have been associated with XLID (Neri et al. 2018. PubMed ID: 29696803). Testing a large panel of genes as well as using a trio approach (testing parents) is known to have higher diagnostic yield due to the extreme clinical and genetic heterogeneity of intellectual disability (Vissers et al. 2016. PubMed ID: 26503795).

Single nucleotide variants (SNVs) are the most common type of variant known to cause TAF1-related XLID (Human Gene Mutation Database), therefore analytical sensitivity for TAF1 SNVs is expected to be very high. Large duplications of TAF1 are another possible cause (O'Rawe et al. 2015. PubMed ID: 26637982). The reported duplications are large, including multiple genes. Analytical sensitivity using our NGS-CNV detection method is expected to be close to 100% for this type of large duplication. In summary, this test is expected to detect nearly all clinically relevant variants in TAF1.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the TAF1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or 2x Sanger sequencing.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).