ClinVar

Description

The deletion of Xq28 is reciprocal to the recurrent Xq28 microduplication syndrome region (OMIM 300815), and both are mediated by nonallelic homologous recombination between two directly oriented int22h repeats. Haploinsufficiency of F8 (OMIM 300841), in males, is associated with hemophilia A (OMIM 306700). While female carriers are generally considered to be unaffected, 30% of heterozygous females have clotting activity below 40% and are at risk for increased bleeding (Konkle 2000). Additionally, haploinsufficiency of RAB39B (OMIM 300774) is associated with X-linked intellectual developmental disorder 72 (XLID72; OMIM 300271) while missense and loss-of-function variants of RAB39B have been associated with X-linked Waisman syndrome (WSMN; OMIM 311510), which is characterized by delayed psychomotor development, impaired intellectual development, and early-onset Parkinson disease. Further, hemizygous missense variants of CLIC2 (OMIM 300138) have been identified in individuals with X-linked syndromic intellectual developmental disorder-32 (OMIM 300886). Hemizygous deletions involving BRCC3 (OMIM 300617) and MTCP1 (OMIM 300116) has been identified as an etiology for Moyamoya disease 4 (MYMY4; OMIM 300845). Unlike Xq28 microduplication which is characterized by cognitive impairment, behavioral problems, and distinctive facial features in affected males and milder phenotypes in female carriers, the reciprocal deletion in males has been proposed to result in X-linked fetal lethality, with female carriers being reportedly unaffected due to skewed chromosome X inactivation (El-Hattab 2011, El-Hattab 2015). As copy number losses of this interval have been associated with a clinical phenotype, and there are no similar copy number losses of this region in the general populations of the Database of Genomic Variants, based on current medical literature and gene content, this copy number variant (CNV) is classified as pathogenic, with clinical presentation of this finding in a female typically being dependent upon X-inactivation status. References: El-Hattab et al., J Med Genet. 2011 Dec;48(12):840-50. PMID:21984752 El-Hattab et al., BMC Med Genet. 2015 Mar 14;16:12. PMID: 25927380 Konkle et al., GeneReviews. 2000 Sep; NBK1404. PMID: 20301578