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.
- Carrier testing in adults with a family history of NEXMIF-Related X-linked Mental Retardation.
PCR amplification of 3 exons contained in the NEXMIF gene is performed on the patient's genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient's gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.
Clinical Sensitivity: Unknown. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's clinical and/or biochemical phenotype.
Analytical Sensitivity: ~99%
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
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
- Deletion/duplication analysis of the NEXMIF gene by CGH array is available for those individuals in whom sequence analysis is negative.
- 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.