Mutations in the ACSL4, also know as FACL4, gene (Xq22.3) have been associated with severe non-syndromic X-linked intellectual disability. Affected males show nonspecific, nonprogressive intellectual disability, ranging from severe to moderate without seizures, whereas carrier females showed highly variable cognitive capacities, ranging from moderate intellectual disability to normal intelligence. ACSL4 deletions have also been found in patients with Alport syndrome, elliptocytosis, and intellectual disability.
Long chain acyl-CoA synthetase (LACS) or long chain fatty acid-CoA ligase (FACL) converts free long chain fatty acids into fatty acyl-CoA esters, which are key intermediates in the synthesis of complex lipids. The ACSL4/FACL4 gene encodes a form of LACS and is expressed in several tissues, including the brain. Both point mutations and deletions have been reported in the gene. Reduction of FACL activity may lead to deranged fatty acid metabolism in neurons, causing defects of neuron outgrowth, synaptogenesis, and other developmental functions important for normal brain development.
For patients with a suspected ACSL4-related disorder, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.
This test is indicated for:
- Confirmation of a clinical/biochemical diagnosis of an ACSL4/FACL4-related disorder.
- Carrier testing in adult females with a family history of an ACSL4/FACL4-related disorder.
PCR amplification of 14 exons contained in the ACSL4/FACL4 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, other regulatory element mutations, and large deletions will not be detected by this analysis.
Analytical Sensitivity: ~99%.
Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.
Submit only 1 of the following specimen types
Preferred specimen type: Whole Blood
Type: Whole Blood
Specimen Requirements:In EDTA (purple top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml
Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.
Specimen Requirements:OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.
Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.
- ACSL4 deletion/duplication analysis (RY) is available for those individuals in whom sequence analysis is negative.
- An X-Linked Intellectual Disability panel with sequencing and deletion/duplication analysis of 110 genes is available.
- Known Mutation Analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
- Prenatal Custom Diagnostics is available to adult females who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.