MSL3, located on chromosome Xp22.2, encodes chromatin-associated male specific lethal (MSL) complex subunit 3, which is responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. MSL3 protein plays a critical role in a dosage-compensation pathway, equalizing X-linked gene expression in males and females.
MSL3 variants have been detected in unrelated patients with global developmental delay (PMID: 28135719), and further specifically identified to cause Basilicata-Akhtar syndrome (PMIDs: 30224647, 33173220).
Clinical features of the syndrome include progressive gait disturbance, recognizable facial dysmorphism, hypotonia, feeding difficulties in early infancy, global delay in the acquisition of major milestones including walking and speech, and intellectual disability.
MSL3 variants lead to a heterogeneous pattern in patient cells compared to homogeneous intensity in control cells. Cells lacking functional MSL3 displayed a severe decrease in H4K16ac. In general, MSL3 causes an acute downregulation of numerous biologically relevant genes, including key developmental regulators. Some of the transcriptional and cellular phenotypes in patient cells are rescued by histone decetylase inhibitors (PMID: 30224647).
Based on the consistent phenotypes in a high number of unrelated patients harboring MSL3 variants reported across studies (PMIDs: 30224647, 33173220), and clear experimental evidence of the role of MSL3 in developmental processes, MSL3 is definitively associated with Basilicata-Akhtar syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 18, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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