X-Linked Intellectual Disability via the UBE2A Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
10451 UBE2A 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
10451UBE2A81479 81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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.

Genetics

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).

Clinical Sensitivity - Sequencing with CNV PGxome

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.

Testing Strategy

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. 

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

This test is appropriate for patients with X-linked intellectual disability who are negative for chromosomal abnormalities, copy number variations, and Fragile-X syndrome. Yet this gene may be more commonly tested as part of a larger panel or exome test, unless clinical knowledge, such as a strongly overlapping facial gestalt, implicates UBE2A. Targeted testing is indicated for family members of patients who have a known pathogenic variant in UBE2A.

Gene

Official Gene Symbol OMIM ID
UBE2A 312180
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Comprehensive Epilepsy and Seizure Panel
Intellectual Disability, Epilepsy, and Autism (IDEA) Panel
X-Linked Intellectual Disability Panel

Citations

  • Bruinsma et al. 2016. PubMed ID: 26476408
  • Budny et al. 2010. PubMed ID: 20412111
  • Czeschik et al. 2013. PubMed ID: 24053514
  • de Leeuw et al. 2010. PubMed ID: 21108393
  • Human Gene Mutation Database (Bio-base).
  • Nascimento et al. 2006. PubMed ID: 16909393
  • Neri et al. 2018. PubMed ID: 29696803
  • Online Gene Essentiality (OGEE).
  • Stevenson et al. 2019. PubMed ID: 30179896
  • Tsurusaki et al. 2017. PubMed ID: 28611923
  • Vissers et al. 2016. PubMed ID: 26503795

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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