Intellectual Disability via the ACSL4 Gene

X-linked Intellectual Disability (XLID) contributes almost 10-15% of intellectual disability (ID) cases in males. Mental Retardation X-linked 63, MRX63 (alternately recognized as MRX68) is a condition of non-syndromic XLID that affects males and rarely carrier females (Raynaud et al. 2000). The skewed X-inactivation in favor of the normal X-chromosome among carrier females indicates the survival influence of the causal gene for MRX63 (Raynaud et al. 2000; Meloni et al. 2002). Affected males display mild to severe non-progressive intellectual disabilities (neurocognitive abnormalities) that is rarely associated with autistic features, but without seizures or facial dysmorphisms (Longo et al. 2003). Interestingly, carrier females have highly variable cognitive capacities, ranging from normal intelligence to moderate intellectual disabilities (Meloni et al. 2002).

Pathogenic variants in ACYL-CoA Synthetase Long Chain Family Member 4, ACSL4 (also known as FACL4) have been reported in multiple families with MRX63. ACSL4 maps to chromosome Xq23. The brain-specific isoform of ACSL4 is the longest isoform that consists of 17 exons and encodes a 711 amino acid polypeptide. ACSL4 is highly expressed in adult human brain, especially in the cerebellar and hippocampal neurons, but not in the glial cells. Loss-of-function variants in ACSL4 abolish the catalytic activity of the enzyme, thus leading to MRX63 due to the deficiency of arachidonyl-CoA esters in the brain (Meloni et al. 2002). Nonsense, missense, splicing variants, and one multi-gene deletion including ACLS4 have been reported. The disease transmission pattern is primarily X-linked recessive.

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 100 genes have been identified in individuals with X-linked intellectual disability (XLID), a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016). Analytical sensitivity should be high because the majority of pathogenic variants reported to date are detectable by sequencing.

To date, there is only one report of a major gross deletion that includes ACSL4 and 8 other genes. Based on this observation, we expect the clinical sensitivity of this test to be low.

This test provides full coverage of all coding exons of the ACSL4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).