X-Linked Intellectual Disability Type 99 via the USP9X 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
13345 USP9X 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
13345USP9X81479 81479 $890 Order Options and Pricing

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Targeted Testing

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

Turnaround Time

18 days on average

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Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

USP9X-related X-linked intellectual disability (USP9X-XLID) affects both males and females. Developmental delay and intellectual disability are the primary features of this disorder, and are observed in all affected individuals. Growth delays and brain malformations are also seen in a majority of patients, both male and female, and can have a prenatal onset. When discussing finer details of the clinical presentation, it is important to distinguish between the male and female forms of this X-linked disorder.

Affected females typically carry de novo loss of function variants (nonsense, frameshift, and canonical-splice altering variants). Along with the neurodevelopmental delays observed in all patients, over half of affected females also present with brain malformations (77%), dental abnormalities (71%), scoliosis (65%), hearing loss (65%), pigmentary abnormalities (65%), eye abnormalities (59%), short stature (53%), post-axial polydactyly (53%), anal atresia (53%), and recurrent respiratory tract infections (53%). Intellectual disability of affected females ranges from mild to moderate, and is associated with motor and language delays in all patients. Brain malformations observed in females are variable, but frequently include hypoplastic corpus callosum, asymmetrically enlarged ventricles, asymmetric cerebellar hypoplasia, abnormal frontal lobe gyration pattern, Dandy-Walker malformation, and thin brainstem. Additional features seen in 20-50% of affected females include hypotonia, hip dysplasia, leg-length discrepancy, heart defects, choanal atresia, thyroid hormone abnormalities, cleft palate or bifid uvula, hypertrichosis, asymmetric hypomastia, urogenital abnormalities, sacral dimple, and seizures. Asymmetric features observed in females (including asymmetry of facial features, brain defects, leg length, and hypomastia) are suspected to be due to variable patterns of X-inactivation in different tissues (see Genetics section). Features seen in less than 20% of affected females include malignancies, and abdominal wall abnormalities. Shared facial features of affected females include asymmetry, prominent forehead, bitemporal narrowing, short palpebral fissures, low nasal bridge, prominent nose, thin upper lip, long and smooth philtrum, and low-set posteriorly rotated or dysplastic ears. Hand and foot abnormalities are also common and include ulnar deviation of the fifth digit, abnormal palmar crease, tapered fingers, short fourth and fifth metacarpals, hallux valgus, sandal gap, and pes cavus. Pigmentary abnormalities frequently follow the lines of Blaschko (Reijnders. 2016. PubMed ID: 26833328).

Affected males can carry de novo or inherited missense variants in USP9X. In addition to neurodevelopmental delays (intellectual disability, speech and language delay, motor problems), all affected males also have variable brain malformations and behavioral problems (Johnson et al. 2020. PubMed ID: 31443933). Brain malformations frequently include white matter abnormalities, dysplastic corpus callosum, and enlarged ventricles, while characteristic behavioral problems include autism, obsessions, attention deficit, anxiety, and aggression. Delays are described as severe in over half of affected males, and ~1/3 of males remain completely nonverbal. Other features seen in over half of affected males include visual system defects (82%), joint hypermobility (79%), gastrointestinal issues (79%), and growth delays (67%). Facial features of affected males are ubiquitously described as dysmorphic; however there is no characteristic facial gestalt. Digital defects include tapered fingers and ulnar deviation of the fifth digit. While the phenotype of male patients has notable overlap with that of females, conspicuously absent in males are the major congenital anomalies. Brain defects and prenatal growth deficiencies are the primary phenotypes reported before birth for affected males. Language abilities in males range from mild apraxia to completely nonverbal.

USP9X-XLID is a rare disorder, with less than 100 patients documented in the literature. While there is no treatment for this disorder, advantages of testing may include prognostic information, early identification and treatment of symptoms such as autism, seizures, and malignancies, and ability to join USP9X family support groups. 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

Literature evidence supports both X-linked dominant and X-linked recessive inheritance patterns for USP9X-associated XLID. Most affected females carry de novo loss of function variants (including nonsense, canonical splice-altering, frameshift, and large deletion variants). Studies in humans suggest that USP9X escapes X-inactivation; however, many genes only achieve partial escape. In line with this, some evidence suggests that tissue-specific or partial X-inactivation may affect the presentation and severity of the disease in females, particularly resulting in asymmetric phenotypes (Reijnders. 2016. PubMed ID: 26833328). Affected males can have hemizygous de novo variants, or inherit a pathogenic variant from an unaffected carrier mother. A large majority of pathogenic USP9X variants in males are missense changes. Current literature evidence indicates that female carriers of these missense changes are completely unaffected, suggesting a completely X-linked recessive inheritance mode for missense alterations (Johnson et al. 2020. PubMed ID: 31443933). Due to this gene’s escape from X-inactivation, we would not expect female phenotype to depend on X-inactivation skewing, as seen with other X-linked recessive conditions; however, extensive studies have not been done to rule out potential carrier phenotypes of pathogenic missense alterations. On the whole, due to X-inactivation escape, X-inactivation studies of females are unlikely to be useful when assessing the significance of a USP9X variant during family segregation studies (Reijnders. 2016. PubMed ID: 26833328).

USP9X is located at Xp11.4, consists of 45 exons, and codes for a 2570 amino acid protein (NM_001039590). USP9X stands for Ubiquitin-Specific Protease 9, X-linked, and serves as a substrate-specific deubiquitylating enzyme. The USP9X protein (probable ubiquitin carboxyl-terminal hydrolase FAF-X) has defined roles in many stages of neuronal development, and is essential for survival in mice. Conditional mouse knockouts eliminating Usp9x in the forebrain show a partial recapitulation of the human phenotype with agenesis of the corpus callosum, and other brain malformations, along with learning and memory deficits, motor, muscular, and visual system defects (Johnson et al. 2020. PubMed ID: 31443933).

Pathogenic USP9X variants are widely spread throughout the gene (Johnson et al. 2020. PubMed ID: 31443933). The gene contains a deubiquitylating catalytic domain, but no dramatic clustering of pathogenic changes in this region or any other segment of the gene has been appreciated to date, and no founder variants have been identified. Notably, loss of function variants are extremely rare in males and restricted to the end of the protein when seen, suggesting that complete loss of USP9X function is likely to be embryonic lethal, as seen in mice. Penetrance of USP9X-XLID is currently thought to be 100%, and in line with this, variants documented as pathogenic are completely absent from the gnomAD database. Due to the X-linked recessive inheritance in males, we would expect some true causative variants to be present in gnomAD in the heterozygous state; however, currently only variants of uncertain significance are documented in gnomAD. On the whole, this gene is highly intolerant loss of function variation in the heterozygous state (https://gnomad.broadinstitute.org/).

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic variants in USP9X are expected to account for <0.1% of cases of intellectual disability (ID), and less than 2% 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 USP9X-related XLID (Human Gene Mutation Database), therefore analytical sensitivity for USP9X SNVs is expected to be very high. Large deletions of USP9X are another documented cause of USP9X-XLID (Reijnders. 2016. PubMed ID: 26833328). The reported deletions include multiple exons or the entire gene. 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 variant types in USP9X.

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 USP9X 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. Targeted testing is indicated for family members of patients who have a known pathogenic variant in USP9X.

Gene

Official Gene Symbol OMIM ID
USP9X 300072
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Intellectual Disability, Epilepsy, and Autism (IDEA) Panel
Top 99 Genetic Causes of Developmental Delay Panel
X-Linked Intellectual Disability Panel

Citations

  • Human Gene Mutation Database (Biobase).
  • Johnson et al. 2020. PubMed ID: 31443933
  • Neri et al. 2018. PubMed ID: 29696803
  • Reijnders. 2016. PubMed ID: 26833328
  • Vissers et al. 2016. PubMed ID: 26503795

Ordering/Specimens

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