ClinGen Dosage Sensitivity Curation Page

Xq28 recurrent region (int22h1/int22h2-flanked) (includes RAB39B)

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
25927380 El-Hattab et al. (2015) summarize clinical findings of three female carriers from two families with the reciprocal deletion of the int22h1/int22h2-mediated Xq28 duplication syndrome region. A proband (case 6), referred for obesity, and her mother, who was also overweight, both had normal cognition. The mother had a history that included a spontaneous miscarriage at 12 weeks. An additional female patient (case 7) was diagnosed prenatally with referral for AMA; the 3 month old infant was healthy. Notably, the phenotypes associated with nullisomy for F8 (hemophilia A) and deletion of the adjacent region containing genes FUNDC2, CMC4, MTCP1, and BRCC3 (syndromic Moyamoya disease), genes that are contained within this region, were not observed in any of these patients.
21984752 El-Hattab et al. (2011) describe the int22h1/int22h2-flanked deletion "in a girl and her mother, both of whom exhibit normal cognition and completely skewed XCI. The mother also had two spontaneous abortions." The authors propose, "This observation coupled with the fact that this deletion has not been identified in males suggests that such deletions may be lethal for males in utero."

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

Evidence for triplosensitivity phenotype
PubMed ID Description
25927380 El-Hattab et al. (2015) summarize the clinical findings of five males and six females (from five families) with int22h1/int22h2-mediated Xq28 duplications. "The males manifested cognitive impairment, behavioral problems, and distinctive facial features. Two of the six females manifested mild cognitive impairment." Parental testing was performed in three of families, and in each case, the duplication was found to be maternally inherited. Of note, four of the six females who carried the duplication were found to have skewed X-chromosome inactivation. The presence of skewed X-chromosome inactivation was not found to correlate with the presence of cognitive impairment in the reported carrier females.
21984752 El-Hattab et al. (2011) describe the int22h1/int22h2-flanked duplication in four males (from three families). The four male patients were cognitively impaired and shared "behavioral abnormalities (hyperactivity and aggressiveness) and characteristic facial features (high forehead, upper eyelid fullness, broad nasal bridge and thick lower lip)." In each of the three families, the duplications were inherited from the mother who presented with cognitive impairment and had skewed chromosome X-inactivation.
24357492 Vanmarsenille et al. (2013) describe the int22h1/int22h2-flanked duplication in four males (from three families). The four male patients were found to have mild/moderate intellectual disability, developmental delay, learning difficulties, behavioral problems, and variable dysmorphic facial features. Parental testing was performed in two of the three families, and in both cases the duplication was found to be maternally inherited. Of note, one of these mothers was reported to have had learning difficulties and showed random X-inactivation in lymphocytes. The second mother showed skewed X-inactivation, but had no clinical information reported.

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.