Childhood onset hereditary spastic paraplegia

Gene: ACBD6

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 26 Sep 2024, 1:01 p.m. | Last Modified: 26 Sep 2024, 1:01 p.m.

Panel Version: 6.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on phenotypes: This gene now has a relevant phenotype listed in OMIM (MIM# 620785)

Created: 23 Apr 2024, 1:37 p.m. | Last Modified: 23 Apr 2024, 1:37 p.m.

Panel Version: 4.43

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Created: 17 Jan 2024, 5:22 p.m. | Last Modified: 17 Jan 2024, 5:22 p.m.

Panel Version: 5.405

- PMID: 21937992 (2011) - single individuals with a p.G22fs variant in the ACBD6 gene, presenting with mild ID, microcephaly, facial dysmorphism, spasticity. Limited additional information.

- PMID: 32108178 (2020) - two unrelated individuals with neurodevelopmental disorder (moderate ID is noted but otherwise limited clinical information) and carrying homozygous LoF variants in the ACBD6 gene (1 frameshift, 1 canonical splice). One individual also carried an allelic homozygous variant in the PRDX6 gene (unlikely but unknown disease consequence). Skin-derived patient fibroblasts showed reduced ACBD6 expression and N-myristoylation deficiency.

- PMID: 36457943 (2023) - two Thai siblings presenting with profound ID, morbid obesity, pancytopenia with severe recurrent infections, diabetes mellitus, cirrhosis, and renal failure, leading to deaths in their early 30s. Sequencing showed a novel homozygous single bp duplication (c.360dup; p.Leu121Thrfs*27) in the ACBD6 gene. Parents were heterozygous carriers.

- PMID: 37951597 (2023) - 45 previously undiagnosed individuals from 28 families with a neurodevelopmental syndrome including a complex and progressive movement disorder phenotype. Cardinal clinical features include moderate-to-severe GDD/ID (45/45), facial dysmorphism (38/40), HC <2nd percentile (21/31), weight >50th percentile (20/34), mild cerebellar ataxia (35/41), limb spasticity/hypertonia (31/41), gait abnormalities (33/35), dystonia (30/32) and variable epilepsy (13/29).

Homozygous ACBD6 variants were identified by WES in all cases, including 18 predicted LoF, 1 missense and 1 inframe insertion. Knockout studies in zebrafish recapitulate clinical features reported in patients such as movement disorders, seizures, and facial dysmorphology, while inactivation of acbd6 in X. tropicalis predominantly caused embryo death while surviving tadpoles demonstrated microcephaly, reduced movement, eye abnormalities, and brain structure differences.

Created: 17 Jan 2024, 5:12 p.m. | Last Modified: 17 Jan 2024, 5:12 p.m.

Panel Version: 5.402

Comment on publications: PMID: 32108178 (2020) paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques

Created: 17 Jan 2024, 3:58 p.m. | Last Modified: 17 Jan 2024, 3:58 p.m.

Panel Version: 5.402

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder, MONDO:0700092

Publications

• 21937992
• 32108178
• 36457943
• 37951597

Red List (low evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
AUTOSOMAL RECESSIVE MENTAL RETARDATION

Publications

• 21937992

I don't know

ACBD6 variants have not been associated with a phenotype in OMIM, and as an autosomal recessive condition with Limited strength in Gen2Phen. Three variants have been reported in three unrelated cases with intellectual disability, however, in one of these carriers the ACBD6 variant was allelic with PRDX6 gene c.136del; p.(ValCysfs*23), therefore the contribution of the ACBD6 variant to intellectual disability is uncertain in this case (PMID: 21937992, 32108178).

Created: 15 Jan 2024, 3:31 p.m. | Last Modified: 15 Jan 2024, 3:31 p.m.

Panel Version: 5.400

Single variant found as only change in one ID family

Created: 31 Oct 2017, 9:57 a.m.

Phenotypes
Intellectual disability

Publications

• 21937992

Red List (low evidence)