ClinVar Genomic variation as it relates to human health

The large Xp22.11p21.1 deletion involves multiple protein-coding genes, including multiple genes associated with X-linked disorders: ARX (OMIM 300382), GK (OMIM 300474), IL1RAPL1 (OMIM 300206), NR0B1 (OMIM 300473), and multiple exons of the 3-prime portion of DMD (OMIM 300377; NM_004006.3) and POLA1 (OMIM 312040; NM_016937.4). Deletions overlapping this region are associated with chromosome Xp21 deletion syndrome (OMIM 300679), a rare contiguous gene deletion syndrome characterized by co-occurrence of disorders such as congenital adrenal hypoplasia, Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, ornithine transcarbamylase deficiency, glycerol kinase deficiency, and intellectual disability (Rathnasiri 2021, Koh 2013, Sevim 2011, Stanczak 2007). The clinical features depend on the size and gene content of the deleted interval. In males, haploinsufficiency of some of the genes in this interval would be expected to result in glycerol kinase deficiency (GK; OMIM 300474), Duchenne muscular dystrophy (DMD; OMIM 310200), congenital adrenal hypoplasia (AHC; OMIM 300200), intellectual developmental disorder-21 (XLID21; OMIM 300143), lissencephaly-2 (LISX2; OMIM 300215), and possibly other X-linked disorders. More than 100 male patients have been reported so far, while only a few symptomatic female carriers have been described due skewed X-chromosome inactivation (Heide 2015, Shaikh 2008). Symptomatic female carriers of a pathogenic Xp21 deletion can present with some aspects of the phenotypic and developmental abnormalities seen in males. Norman and Harper reported that 2.5% of the DMD carriers have clinical evidence of a muscle disease (1989). Thus, clinical consequence of this pathogenic copy number variant (CNV) in females is unclear. References: Heide et al. Eur J Med Genet. 2015 Jun-Jul;58(6-7):341-5. PMID: 25917374. Karaca et al., Neuron. 2015 Nov 4;88(3):499-513. PMID: 26539891. Koh et al., Ann Pediatr Endocrinol Metab. 2013 Jun;18(2):90-4. PMID: 24904859. Rathnasiri et al., BMC Endocr Disord. 2021 Oct 24;21(1):214. PMID: 34689766. Sevim et al., J Pediatr Endocrinol Metab. 2011;24(11-12):1095-8. PMID: 22308874. Shaikh et al., J Med Genet. 2008;45 (9). PMID: 18762570. Stanczak et al., Hum Mutat. 2007 Mar;28(3):235-42. PMID: 17089405.