Two Chinese patients with Basilicata-Akhtar syndrome caused by novel MSL3 variants: a case report and literature...

MSL3 is a subunit of the chromatin-associated male-specific lethal (MSL) complex that regulates global histone H4 lysine-16 acetylation (H4K16ac) that plays a critical role as an epigenetic regulator in flies and mammals. Variants of MSL3 have been reported to cause an ultra-rare developmental disorder, Basilicata-Akhtar syndrome (MRXSBA) (OMIM #301032), which is characterized by global development delay, intellectual disability (ID), muscular hypotonia and progressive spasticity. To date, only 42 patients with MRXSBA have been reported around the world, and the diagnosis and treatment of MRXSBA remain challenging.

We present two cases: an 8-year-old girl and a 4-year-11-month-old boy. Two patients mainly exhibiting slightly ID and slightly dysmorphic facial features received a diagnosis of MRXSBA. The next generation sequencing identified two damaging novel MSL3 variants in two individuals, including one nonsense variant (c.570C>G, p. Tyr190*) and one splicing variant (c.1466+2T>C), which were validated by Sanger sequencing. They all affected the morf-related gene (MRG) domain of MSL3, consistent with all deleterious variants previously reported. The phenotypes of Chinese patients with MRXSBA were summarized and compared to MRXSBA patients of other ethnicities reported previously. Hypotonia and macrocephaly prevalence were markedly higher in individuals of other ethnicities, while other clinical phenotypes demonstrated comparable frequencies. Four novel phenotypic characteristics of MRXSBA individuals were identified, including growth hormone deficiency (GHD), slow growth of permanent teeth, scoliosis, and cleft palate. The individual with GHD received recombinant human growth hormone (rhGH) treatment and underwent long-term follow-up exceeding 10 years during routine clinic visits. He demonstrated good height improvement following rhGH treatment. No secondary adverse effects were observed.

Our study expands the genotypic and phenotypic spectrum of Basilicata-Akhtar syndrome. Our data support the notion that the MRG domain of MSL3 is intolerant to loss-of-function variants and responsible for MSL3 function. Over 10 years of clinical follow-up indicates that rhGH treatment could be an option to improve the height in individuals with MRXSBA and GHD. Our study lays an important foundation for the precise diagnosis and therapeutic approaches of MRXSBA.