ClinGen Dosage Sensitivity Curation Page

USP9X

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
26833328 A multi-institutional study identified 17 females with de novo loss-of-function mutations in USP9X and presenting with ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations. Transcript and protein studies confirmed loss of function effect as a result of the mutations.
24607389 Report describes three variants (two missense and one protein truncating) in USP9X in females with syndromic intellectual disability. Loss of Usp9x in mice causes reduction in both axonal growth and neuronal cell migration. In family 1, a missense variant (c.6278T>A, p.Leu2093His) was found in a singleton affected male. In family 2, a second missense variant (c.6469C>A, p.Leu2157Ile) was found in an affected male, his unaffected mother, and his unaffected grandmother. The proband in this second family also had a ?790 kb deletion at 6q25.3, which includes ARID1B. However, parental testing was not performed to determine if it was de novo (as many ARID1B mutations are). In a third family, a single-nucleotide deletion (c.7574delA, p.Gln2525Argfs?18) was identified in two half brothers, their unaffected mother and affected uncle, and their unaffected grandmother. Important to note - the truncating mutation was in the last exon and therefore might escape NMD. The authors showed that overexpression of wild-type human USP9X in. mutant Usp9x mice rescued defects, but all three USP9X variants listed above failed to rescue axonal growth, caused reduced USP9X protein localization in axonal growth cones, and (in 2/3 variants) failed to rescue neuronal cell migration.
28377321 Report describes two female individuals with ID and various congenital anomalies, reminiscent of UPS9X phenotype (heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, abnormal pigmentation along lines of Blaschko, and Dandy Walker malformation). Phenotype overlaps that of CHARGE syndrome and some ciliopathies such as Joubert and Bardet-Biedl. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion that was associated with a deletion of the 5'UTR of the USP9X. The second individual had a de novo frameshift mutation detected by whole-exome sequencing (c.4104_4105del, p.Arg1368Serfs*2).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for Triplosenstive Phenotype

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.