SUPT16H-Related Intellectual Disability via the SUPT16H Gene

SUPT16H syndrome is characterized by intellectual disability and developmental delay, manifesting either prenatally or in infancy. Most affected individuals learn to walk, but a majority never gain meaningful language abilities. Very few patients have been described, however all known pathogenic variants have occurred de novo, and the disorder affects males and females equally. All affected individuals have gross motor delays, speech and language delay, and intellectual disability. As is typical of neurodevelopmental disorders, other features of SUPT16H syndrome are more variable. Feeding difficulties in infancy, sleep disturbances, and brain malformations including dysplastic corpora callosa and decreased white matter volume are seen in a majority of patients. Other phenotypes seen in less than half of patients include seizures, autistic features, precocious puberty, congenital heart defects, and constipation. There is not a recognizable facial gestalt, however some shared features include frontal bossing, abnormal head shape, dysplastic ears, hypertelorism, down-slanting palpebral fissures, broad nasal bridge, and bifid uvula (Bina et al. 2020. PubMed ID: 31924697). 

SUPT16H syndrome is expected to be a very rare disorder. There are no treatments for SUPT16H syndrome, yet patients and their families may benefit from a molecular diagnosis for prognostic information, early identification and treatment of symptoms (such as feeding difficulties or precocious puberty), or for connecting with other affected individuals and relevant research or support groups. For some, knowledge of a de novo variant and the associated reduced recurrence risk may ease anxiety for future reproductive planning.

SUPT16H intellectual disability is an autosomal dominant disorder, caused by de novo variants in the SUPT16H gene. A majority of the known pathogenic variants are missense alterations, which are spread throughout the gene with no apparent clustering in functional domains. The gene as a whole is also intolerant of missense changes according to mathematical models comparing the missense variants observed in the gnomAD database to the number expected based on gene size. In addition, several large deletions including the SUPT16H gene have also been documented as pathogenic (Zahir et al. 2007. PubMed ID: 17545556; Bina et al. 2020. PubMed ID: 31924697). Notably, frameshift and nonsense changes in SUPT16H are extremely rare in public databases, suggesting that a majority of SUPT16H loss of function alterations may be lethal (gnomAD). To our knowledge, no animal models of SUPT16H loss or gain of function variants have been characterized in the literature.

SUPT16H is a subunit of the FACT complex (facilitates chromatin remodeling) and homolog of S. Cerevisiae SPT16. SUPT16H is localized to the nucleus, and widely expressed throughout most tissues. This complex is critical to DNA transcription, replication, and repair. In more detail, the FACT complex works to destabilize, and then subsequently repair the structure of the histones of nucleosomes in order for other cellular machinery like RNA polymerase II to be able to access the DNA. SUPT16H is located at 14q11.2, consists of 26 exons, and codes for a 1047 amino acid protein (NM_007192). Only one isoform of SUPT16H is known to be significantly expressed (UniProt, Ensembl). SUPT16H has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

The diagnostic yield of this test for individuals with syndromic intellectual disability is predicted to be very low (<0.1%), however no large cohorts estimating clinical sensitivity have been published for this gene. It is important to note the high clinical and genetic heterogeneity of intellectual disability, and improved diagnostic yields that result from testing large panels of genes as well as testing parents along with the patient using a trio approach. The analytical sensitivity of this test is expected to be high, as it will detect all types of SUPT16H variants identified to date, including missense variants as well as multiple-exon deletions or duplications.

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 SUPT16H 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).