Contiguous Gene Syndromes at Xp21

Close to 100 patients with Xp21 contiguous deletion syndromes have been reported (81-84). About two-thirds of the patients have DMD, glycerol kinase deficiency (GKD; MIM 307030), and adrenal hypoplasia congenital (AHC; MIM 300200), 25% have AHC and GKD, and the rest have GKD and DMD, or the more proximally located disorders such as the McLeod phenotype (MIM 314850), chronic granulomatous disease (CGD; MIM 306400), and ornithine transcarbamylase (OTC) deficiency (MIM 311250). AHC is caused by defects in the nuclear receptor subfamily 0 group B, member 1 (NROB1) gene, also known as DAX1, which when present in double dosage causes XY sex reversal (85,86). CGD is caused by defects in the cytochrome b P subunit (CYBB) gene (87). The sizes of the deletions range from less than 1 Mb to more than 14 Mb, and the deletion breakpoints spread over a wide range (Fig. 3B) (81). A boy with AHC and mental retardation was reported to have a 2-Mb deletion extending from the NR0B1 gene to the distal interleukin-1 receptor accessory protein-like (IL1RAPL) gene, which is 1.4 Mb in size (84), implicating IL1RAPL in nonspecific mental retardation. None of the deletion breakpoints have been isolated and the mechanism(s) underlying the deletions remains unclear.

Fig. 3. Contiguous gene syndromes at two regions of the X chromosome. The maps show the distances (in megabases) of the genes from Xp telomere, taken from the NCBI map viewer. Not all genes in the areas are shown. Lines at the left side of the maps depict regions deleted in the patients. A line in most cases represents deletions in a collection of patients who have the same phenotype but different deletion breakpoints. The dashed ends of the line cover the regions where the breakpoints may be located since most breakpoints of the deletions have not been well mapped. PAR1, pseudoautosomal region 1; SS, short stature; LWD, Leri-Weill dyschondrosteosis; CDPX, X-linked chondrodysplasia punctata; MR, mental retardation; XLI, X-linked ichthyosis, KAL1, X-linked Kallmann syndrome; OA1, Ocular albinism type 1; MLS, microphthalmia with linear skin defects; AHC, adrenal hypoplasia congenital; GKD, glycerol kinase deficiency; DMD, Duchenne muscular dystrophy; BMD, Becker muscular dystrophy; CGD, chronic granulomatous disease; OTCD, ornithine transcarbamylase deficiency.

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