ACBD6 – Neurodevelopmental Disorder

The ACBD6 gene, when mutated in a biallelic (autosomal recessive) manner, has been associated with a neurodevelopmental disorder that presents with a complex clinical phenotype. Affected individuals not only manifest neurodevelopmental disruptions but also exhibit additional systemic features including cirrhosis, renal insufficiency, and diabetes mellitus. This expanded phenotype was highlighted in a case report where the syndrome was described in detail, underscoring the relevance of ACBD6 in a broader clinical context (PMID:36457943).

Genetic evidence supporting the association includes the identification of a novel homozygous frameshift mutation, c.360dup (p.Leu121ThrfsTer27), in two affected Thai siblings. This mutation, confirmed via whole-exome sequencing and PCR-Sanger sequencing, disrupts the coding frame of ACBD6, leading to a predicted loss-of-function effect. In addition to this family, previous multi-patient studies have reported biallelic variants in a total of 7 patients with neurodevelopmental disorders, further consolidating the role of ACBD6 in disease pathogenesis (PMID:36457943).

The genetic evidence is bolstered by moderate segregation data; the proband and an affected sibling from the same family share the homozygous variant, and additional unrelated patients have been reported with similar genetic findings. This recurrence of the loss‑of‑function variant within a critical exonic region supports its pathogenicity and reinforces the autosomal recessive mode of inheritance. Although the number of probands is relatively modest, the consistency across independent families provides compelling support for the gene–disease link.

Functional assessments, while not extensively detailed in the supplied evidence, suggest that the frameshift variant results in a truncated protein that likely disrupts normal ACBD6 function. The anticipated loss‑of‑function is consistent with the observed phenotype, although further experimental validation in cellular or animal models would ideally augment the current findings. Nevertheless, the available functional insights align with the genetic data and contribute to establishing the overall clinical validity of the association.

Integrating the genetic and preliminary functional data, the ACBD6–neurodevelopmental disorder association is supported by evidence from both case reports and multi‐patient studies. The observations of a recurrent loss‑of‑function mechanism across multiple families justify a moderate to strong level of clinical confidence, particularly for diagnostic and commercial applications. Further research may enhance the evidence base, but current findings provide a clear basis for including ACBD6 in diagnostic panels for patients with neurodevelopmental disorders and associated metabolic and liver/renal complications.

Key take‑home: Testing for biallelic ACBD6 variants is clinically valuable for patients with complex neurodevelopmental and systemic phenotypes, guiding precise diagnosis and management strategies.

References

• Neurology. Genetics • 2023 • Neurodevelopmental Disorder, Obesity, Pancytopenia, Diabetes Mellitus, Cirrhosis, and Renal Failure in ACBD6-Associated Syndrome: A Case Report PMID:36457943

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