Intellectual disability (ID) is a nonprogressive cognitive impairment affecting 1-3% of the Western population. It is estimated that up to 50% of moderate-severe cases have genetic causes and approximately 10% are due to X-linked intellectual disability disorders (XLID). XLID can be syndromic or nonsyndromic and is observed in all ethnic groups. More than 100 XLID syndromes have been described in the literature to date. Fragile X is the most common XLID syndrome (~1 in 4000 males) while others can be quite rare with only a few patients reported in the literature. Males can have moderate to severe intellectual disability depending on the syndrome, and carrier females can also be affected, but typically have milder clinical symptoms.
Cantagrel et al. describe a family with two affected males with severe intellectual disability. Both males (an uncle and a nephew) presented with neonatal hypotonia, severe developmental delays, progressive quadriparesia, gastroesophageal reflux, autism, steryotypical hand movements, and mildly dysmorphic features. One of the affected individuals had tonic-clonic seizures as well.
A pericentric inversion (inv(X)(p22;q13)) was identified in both males and their unaffected obligate carrier mothers. One of the genes disrupted by the inversion is the NEXMIF (previously known as KIAA2022) gene (Xq13.3) which is highly expressed in fetal brain and adult cerebral cortex. The NEXMIF transcript was no longer expressed in the affected males; however, it was indistinguishable from the wildtype in the cells from the carrier mothers.
- OMIM #300524: NEXMIF gene
- Cantagrel et al. (2004). J Med Genet, 41:736-742
This test is indicated for:
- Confirmation of a clinical diagnosis of NEXMIF-Related X-linked Mental Retardation in an individual in whom sequence analysis was negative.
- Carrier testing in adults with a family history of NEXMIMF-Related X-linked Mental Retardation in an individual in whom sequence analysis was negative.
DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.
Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations. Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
- Sequence analysis of the NEXMIF gene is available and is required before deletion/duplication analysis.
- Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
- Prenatal testing is available only for known familial mutations to individuals who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.
- X-Linked Intellectual Disability panels are available for 30, 60, and 90+ genes.