X-Linked Intellectual Disability via the UBE2A Gene

Pathogenic variants in the UBE2A gene cause syndromic X-linked intellectual disability (XLID), Nascimento-type. This disorder is male-limited and presents in infancy with global developmental delays—including hypotonia, motor delays, mild to severe intellectual disability, and speech delay (100%). A majority of affected males learn to walk before age five, but language abilities remain severely limited into adulthood. A characteristic facial gestalt, seen in a large majority of patients, includes a wide face with mid-face hypoplasia, synophrys, heavy eyebrows, long dense eyelashes, hypertelorism, upslanted palpebral fissures, depressed nasal root, wide mouth with thin lips, short broad neck and low posterior hairline. Over half of affected individuals also have hirsutism (80%), hypogammaglobulinemia (80%), small feet (80%), seizures (70%), small penis (70%), skin abnormalities (70% - described as dry, thick, redundant or myxedematous), wide intermammillary distance (70%), and short stature (50%). Features described in less than half of affected individuals include nail dystrophy (40%), spasticity (30%), hearing loss (25%), heart defects (25%), white matter abnormalities and/or cerebellar hypoplasia (40%), tall stature (20%), micro and macrocephaly (10%, 20%), and behavioral issues (15%) (Stevenson et al. 2019. PubMed ID: 30179896; de Leeuw et al. 2010. PubMed ID: 21108393; Nascimento et al. 2006. PubMed ID: 16909393; Budny et al. 2010. PubMed ID: 20412111; Czeschik et al. 2013. PubMed ID: 24053514; Tsurusaki et al. 2017. PubMed ID: 28611923).

To date, no carrier females have been reported as affected. However, where testing has been done, carrier females have been shown to have skewed X-inactivation patterns (Stevenson et al. 2019. PubMed ID: 30179896; de Leeuw et al. 2010. PubMed ID: 21108393).  

Pathogenic changes in UBE2A are a very rare cause of syndromic XLID, with less than 50 cases reported in the literature to date. While there are no treatments for UBE2A-related intellectual disability syndrome, patients and their families may benefit from a molecular diagnosis for prognostic information, early identification and treatment of symptoms, or for connecting with UBE2A-related XLID support groups. For reproductive planning, families can get maternal testing to determine if a variant arose de novo in the proband, or is present in the maternal germline. 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.

Pathogenic variants in UBE2A cause X-linked recessive syndromic intellectual disability (Nascimento-type). To date, missense, nonsense, frameshift, canonical splice site, and large deletion pathogenic variants have been reported. These are spread widely throughout the gene in all exons, including the terminal exon. No founder or recurrent variants have been identified to our knowledge, and 100% penetrance is expected in males. X-inactivation studies of females may be helpful when assessing the significance of a UBE2A variant during family segregation studies (Stevenson et al. 2019. PubMed ID: 30179896; de Leeuw et al. 2010. PubMed ID: 21108393). The gene as a whole is moderately intolerant to missense variation, and no loss of function changes have been documented in gnomAD, indicating high intolerance to loss of function variation (https://gnomad.broadinstitute.org/).

UBE2A has 6 coding exons and maps to chromosome Xq24, encoding a 152 amino acid protein (NM_003336). Ubiquitin-conjugating Enzyme E2 (UBE2A) is a component of the ubiquitination pathway and in combination with E3-ligating enzymes, catalyzes the covalent attachment of ubiquitin molecules to the substrate proteins, thereby targeting them for degradation by the proteasome complex (Nascimento et al. 2006. PubMed ID: 16909393). A UBE2A hemizygous knockout mouse model at least partially recapitulates the human phenotype – showing learning and memory deficits, but not seizures or motor delays (Bruinsma et al. 2016. PubMed ID: 26476408). UBE2A has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Pathogenic variants in UBE2A 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) and small deletions and duplications are the most common variant types known to cause UBE2A-related XLID (Human Gene Mutation Database). Analytical sensitivity for these small variants is expected to be very high. Large deletions of UBE2A are another documented cause of UBE2A-XLID (Reijnders. 2016. PubMed ID: 26833328). The reported deletions are large, including multiple exons, or multiple genes. Analytical sensitivity using our NGS-CNV detection method is expected to be close to 100% for this type of large deletion. In summary, this test is expected to detect all currently identified causative variant types in UBE2A.

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 UBE2A 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 full coverage as >20X NGS reads or Sanger sequencing.