ClinGen Dosage Sensitivity Curation Page

Xp11.22p11.23 recurrent region (includes SHROOM4)

  • Curation Status: Complete
  • id: ISCA-46290
  • Date last evaluated: 2017-12-14
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 0
  • ClinGen Triplosensitivity Score: 3


Location Information

  • Xp11.22-p11.23
  • GRCh37/hg19 chrX: 48,306,152-52,103,258
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chrX: 48,447,780-52,444,264
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000023.10) ()
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

No cases of reciprocal deletion males have been reported in the medical literature suggesting that it could be male lethal. However, a few cases of non-recurrent deletions have been reported in affected males [PMID:28414775, PMID:25670966]. In these cases, the deletions were inherited from unaffected mothers.

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 gain of function phenotype
PubMed ID Description
19716111 Giorda et al. (2009) describe a recurrent, 4.5Mb duplication that includes numerous OMIM Morbid genes, many of which are linked to X-LMR. These include SYP and SHROOM4. The duplication is bounded by segmental duplications at each end. Phenotypes include speech delay, MR, early puberty, foot anomalies, dysmorphism, abnormal EEG, and seizures. Behavioral abnormalities include shyness, stubbornness, and autistic-like symptoms. Affected females were demonstrated to have skewed X-inactivation. It is suspected that the deletion is non-viable as it has not been detected in any control or clinical populations.
21418194 Edens et al. (2011) describe two females with similar phenotypes: autism and epilepsy. Both had severe intellectual disability. One had skewed X-inactivation but the other had random inactivation. The first case was cytogenetically detectable, but the second had a 5Mb duplication by microarray.
25425167 Nizon et al. (2015) describe 17 new cases ranging in size from 330Kb to 8Mb. Five patients harbored the 4.5?Mb recurrent duplication. Common major characteristics among patients were intellectual disability, early onset of puberty, language impairment, and epilepsy. Atypical breakpoints suggested phenotype/genotype correlations: FTSJ1 and SHROOM4 for intellectual disability and PQBP1 and SLC35A2 for epilepsy.

Triplosensitivity phenotype comment:

The recurrent duplication is approximately 4.5Mb in size, and is flanked distally and proximally by segmental duplications, both containing SSX genes and pseudogenes. Both males and females are affected. Consistent phenotypes have emerged, including intellectual disability, speech and language delay, epilepsy and autistic behaviors.

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.