Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

Abstract

Purpose We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome). Methods Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. Results We 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. Conclusion Our 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.

The best of both worlds: Blending cutting‐edge research with clinical processes for a productive exome clinic

“…Data from this study have been included in 32 publications, including novel gene‐disease associations, 38–46 novel phenotypes 24–28 and phenotype expansions 29–37 for ultra‐rare disorders.…”

“…Most of the 138 definite/likely diagnoses were known disorders (n = 115, 83%); the remaining were new phenotypes for genes previously known to be associated with disease (n = 5, 3.6%) [24][25][26][27][28] and phenotypic expansions for known disorders (n = 9, 6.5%). [29][30][31][32][33][34][35][36][37] Additionally, nine new gene-disease associations (6.5% of the def/likely diagnoses) were established. [38][39][40][41][42][43][44][45][46]…”

“…Data from this study have been included in 32 publications, including novel gene-disease associations, [38][39][40][41][42][43][44][45][46] novel phenotypes [24][25][26][27][28] and phenotype expansions [29][30][31][32][33][34][35][36][37] for ultra-rare disorders. For the fourth patient, the UDN prioritized a homozygous missense variant in a gene that had in the interim been associated with a disease.…”

Novel protein-truncating variants of a chromatin-modifying gene MSL2 in syndromic neurodevelopmental disorders

“…Recent studies of MSL3 , a close family gene of MSL2 , have shed some light into the importance of the MSL complex in neurodevelopment. Pathogenic mutations of MSL3 have been reported in two cohorts with Basilicata-Akhtar syndrome [ 19 , 20 ]. Majority of variants in MSL3 are de novo but rare inherited variants are also observed.…”

MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature

“… 13 De novo variants in another member of the MSL complex, MSL3 (MIM: 300609 ), lead to the Basilicata-Akhtar syndrome (MRXSBA [MIM: 301032 ]), an X-linked condition affecting both sexes and characterized by ID, global DD, hypotonia, gait disturbance, and spasticity. 14 , 15 Primary human dermal fibroblasts taken from individuals with MRXSBA exhibit reduced bulk H4K16ac. 14 …”