Xq28: Cytogenetic Band Location and Clinical Significance
Xq28 designates a specific cytogenetic band located on the long arm (q arm) of the X chromosome at position 28, representing the most distal (telomeric) region of the X chromosome's long arm. 1
Chromosomal Location and Structure
The Xq28 region spans approximately 7.5-12 megabases (Mb) of DNA extending from approximately 8-8.7 Mb proximal to the X chromosome telomere. 1, 2
Nomenclature Breakdown
- X = X chromosome
- q = long arm of the chromosome (as opposed to "p" for short arm) 3
- 28 = band number 28, the most distal band on Xq 1
Clinical Significance
Xq28 contains the highest density of disease-associated genes on the X chromosome, making it one of the most clinically important chromosomal regions in human genetics. 1, 2
Major Disease Loci at Xq28
At least 10-17 genetic diseases map to the Xq28 region, including:
Fragile X syndrome - the most common inherited cause of intellectual disability, with the mutation localized to an interval of 300-700 kilobases between 8 and 8.7 Mb proximal of the Xq telomere 1
Hemophilia A and B - X-linked bleeding disorders 2
Nephrogenic diabetes insipidus (X-linked form) - caused by pathogenic variants in AVPR2 gene located at Xq28, accounting for approximately 90% of all NDI cases 4
G6PD deficiency - with the G6PD locus serving as a landmark for mapping other Xq28 genes 5
Multiple other X-linked conditions including torticollis-keloids-cryptorchidism-renal dysplasia syndrome (mapped distal to G6PD at Xq28) 5
Chromosomal Abnormalities Involving Xq28
Duplications
Xq28 duplications cause a distinct intellectual disability syndrome characterized by:
- Variable cognitive deficits 6
- Distinct facial dysmorphia 6
- Neurobehavioral abnormalities including hyperactivity, irritability, and autistic behavior 6
- More severe manifestations in hemizygous males compared to heterozygous females 6
Int22h1/Int22h2-mediated Xq28 duplication syndrome arises from duplications of the subregion flanked by intron 22 homologous regions 1 and 2, with newly reported features including vertebral anomalies and possible increased malignancy risk. 6
Functional Disomy
Unbalanced X-autosome translocations involving Xq28 result in functional disomy with a recognizable phenotype:
- Severe mental retardation 7
- Wide face, small mouth, thin pointed nose 7
- Major axial hypotonia 7
- Severe feeding problems 7
- Proneness to infections 7
Detection requires clinically oriented FISH study using subtelomeric probes, as these are cryptic rearrangements not visible on routine karyotype. 7
Diagnostic Considerations
Resolution Requirements
Standard G-banding karyotyping (400-550 bands) may miss small Xq28 abnormalities, requiring:
- High-resolution chromosome analysis (850-1000 bands) for better visualization 4, 3
- FISH with locus-specific probes for targeted detection (resolution 30-200 kb) 4
- Chromosomal microarray for submicroscopic alterations <5 Mb 3
- Subtelomeric FISH probes for cryptic terminal rearrangements 4
Clinical Pitfalls
Xq28 abnormalities may be missed because:
- The terminal location lacks distinctive G-bands, making small rearrangements difficult to visualize even at 850-band resolution 4
- Cryptic translocations require specific subtelomeric probe analysis 7
- Partial manifestations in carrier females may be subtle, particularly with X-inactivation patterns 5
When Xq28 abnormalities are suspected based on phenotype (intellectual disability, specific dysmorphic features, X-linked inheritance pattern), proceed directly to targeted FISH or molecular testing rather than relying solely on standard karyotype. 4