ClinGen Dosage Sensitivity Curation Page

HPRT1

  • Curation Status: Complete

Location Information

  • Xq26.2-q26.3
  • GRCh37/hg19 chrX: 133,594,175-133,634,698
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chrX: 134,460,165-134,500,668
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11018746 Jinnah (2000) reviewed 271 inherited mutations causing HPRT deficiency. The cases include over 90 loss of function variants (nonsense variants, splice site varaints, frameshifts and exonic deletions). They show that pathogenic HPRT1 variants are associated with a spectrum of disease that ranges from hyperuricemia alone to hyperuricemia with profound neurological and behavioral dysfunction. Loss of function variants result in the more severe end of the spectrum causing Lesch-Nyhan syndrome and since the disease is inherited in an X-linked recessive manner, nearly all cases were males. However, at least five females with a typical LND phenotype (due to skewed X-inactivation) have been reported. Female carriers although typically unaffected may develop symptoms of hyperuricemia in later years.

Haploinsufficiency phenotype comments:

Lesch-Nyhan syndrome is associated with motor dysfunction resembling severe cerebral palsy, intellectual disability, and self-injurious behavior. Megaloblastic anemia has been found in some patients. Although female carriers are typically unaffected they may develop symptoms of hyperuricemia in later years. See GeneReviews for additional information.

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.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

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.