ClinGen Dosage Sensitivity Curation Page

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

  • Curation Status: Complete
  • id: ISCA-37494
  • Date last evaluated: 2018-08-30
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 3


Location Information

Select assembly: () ()
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency 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."

Haploinsufficiency phenotype comments:

Deletion of the Xq28 int22h1/int22h2-flanked region* in males has been proposed to result in X-linked recessive embryonic/fetal lethality. Female carriers are reportedly unaffected (currently five total are reported in the literature). Supportive evidence includes: reported spontaneous abortion and lack of observation of males in families with carrier females (two carriers of reproductive age are reported) as well as in the clinical population; skewed X-inactivation patterns in carrier females, as well as lack of phenotypic expression of F8-deficiency (bleeding tendency or Hemophilia A) and/or deletion of the FUNCD2-BRCC3 region (syndromic Moyamoya disease). *The distal Xq28 region contains a set of low copy repeats that mediate recurrent rearrangements, including copy number changes through non-allelic homologous recombination. This review refers to deletions involving recurrent breakpoints within the int22h-1 and -2 regions (int22h-1 localizes within intron 22 of the F8 gene). Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region.

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
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.

Triplosensitivity phenotype comment:

Duplication of the Xq28 int22h1/int22h2-flanked region* is associated with syndromic X-linked intellectual disability, characterized in males by variable clinical features that may include: cognitive impairment, behavioral and psychiatric problems, recurrent infections and atopic diseases, obesity, and distinctive facial features. Carrier females have been reported to have a milder phenotype with learning difficulties and distinctive facies, but may also be clinically unaffected. The duplications reported in the literature are typically maternally inherited. *The distal Xq28 region contains a set of low copy repeats that mediate recurrent rearrangements, including copy number changes through non-allelic homologous recombination. This review refers to duplications involving recurrent breakpoints within the int22h-1 and -2 regions (int22h-1 localizes within intron 22 of the F8 gene). Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Additional relevant literature is summarized below: PMID 26962617: GeneReviews: Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated PMID 23299923: Lannoy et al. (2013) reported three unrelated male patients with maternally inherited duplications involving the int22h-1/int22h-2 region. Two males (Cases 1 and 2) were ascertained due to hemophilia A; these patients had complex rearrangements in Xq28 that lead to disruption of F8 and duplication of genes within the int22h1/int22h2-region, characterized by MLPA, long range PCR and arrayCGH. These individuals, as well as other familial carriers were reported to have no intellectual disability or developmental delay. A third non-hemophilic male with int22h1/int22h2-flanked duplication (Case 3) was added to the study. This patient had intellectual disability, Pierre Robin sequence, craniofacial dysmophism, large ears, fetal fingertip pads, rocker bottom feet and pes valgus. The authors noted, "Case 3 displayed dysmorphic features identical to those described [by El-Hattab 2011], with several dissimilar features." The authors argue against an intellectual disability association [possible non-penetrance] for the CNVs identified in cases 1 and 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.