Abstract
PurposeWe sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome). MethodsTwenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. ResultsWe identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. ConclusionOur aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.
Highlights
Demographic features Our cohort of 25 individuals with hemizygous or heterozygous variants in MSL3 includes 15 males and 10 females whose ages ranged from 14 months to 30 years at the time of the last follow-up
Fifteen of 16 (94%) individuals were diagnosed with intellectual disability (ID)
Four of 15 (27%) individuals had received the diagnosis of ID; the level of ID had not been determined
Summary
MSL3 resides on the X-chromosome and encodes a subunit of the chromatin-associated male specific lethal (MSL) complex.[1,2] The MSL complex mediates global histone H4 lysine-16 acetylation (H4K16ac) and plays a crucial role as an epigenetic modulator in flies and mammals.[1,2,3,4] In mammalian species, the core MSL complex consists of MSL1, MSL2, MSL3, and MOF (males absent on the first).[2,3,5] MSL3 itself contains a C-terminal morf-related gene (MRG) domain, responsible for MSL complex formation, and an N-terminal chromo domain (CD), implicated in chromatin targeting.[6,7,8,9,10,11,12]MSL3 was first identified as a candidate gene in the Deciphering Developmental Disorder Study[13] and was recently described as the underlying genetic cause of Basilicata–Akhtar syndrome (MIM 301032), a novel X-linked neurodevelopmental disorder that affects female and male individuals.[14]. MSL3 resides on the X-chromosome and encodes a subunit of the chromatin-associated male specific lethal (MSL) complex.[1,2] The MSL complex mediates global histone H4 lysine-16 acetylation (H4K16ac) and plays a crucial role as an epigenetic modulator in flies and mammals.[1,2,3,4] In mammalian species, the core MSL complex consists of MSL1, MSL2, MSL3, and MOF (males absent on the first).[2,3,5] MSL3 itself contains a C-terminal morf-related gene (MRG) domain, responsible for MSL complex formation, and an N-terminal chromo domain (CD), implicated in chromatin targeting.[6,7,8,9,10,11,12]. Except for the siblings with suspected parental mosaicism and a maternally inherited Xchromosome inversion, all variants occurred de novo. In transfected HEK293 cells, mutant proteins displayed loss of interaction with the histone acetyltransferase MOF and with
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