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

Theresa Brunet, Kirsty McWalter, Katharina Mayerhanser, Grace M. Anbouba, Amy Armstrong-Javors, Ingrid Bader, Evan Baugh, Amber Begtrup, Caleb P. Bupp, Bert L. Callewaert, Anna Cereda, Margot A. Cousin, Juan C.Del Rey Jimenez, Laurie Demmer, Nikita R. Dsouza, Nicole Fleischer, Ralitza H. Gavrilova, Sumedha Ghate, Elisabeth Graf, Andrew GreenSarah R. Green, Maria Iascone, Ameni Kdissa, Dirk Klee, Eric W. Klee, Emily Lancaster, Kristin Lindstrom, Johannes A. Mayr, Meriel McEntagart, Naomi J.L. Meeks, Dana Mittag, Harrison Moore, Anne K. Olsen, Damara Ortiz, Gretchen Parsons, Loren D.M. Pena, Richard E. Person, Sumit Punj, Gonzalo Alonso Ramos-Rivera, Maria J.Guillen Sacoto, G. Bradley Schaefer, Rhonda E. Schnur, Tiana M. Scott, Daryl A. Scott, Carolyn R. Serbinski, Vandana Shashi, Victoria M. Siu, Barbro Fossøy Stadheim, Jennifer A. Sullivan, Jana Švantnerová, Lea Velsher, David S. Wargowski, Ingrid M. Wentzensen, Dagmar Wieczorek, Juliane Winkelmann, Patrick Yap, Michael Zech, Michael T. Zimmermann, Thomas Meitinger, Felix Distelmaier, Matias Wagner

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish
Pages (from-to)384-395
Number of pages12
JournalGenetics in Medicine
Issue number2
StatePublished - Feb 2021


  • MSL3
  • X-linked
  • autism
  • developmental delay
  • histone acetylation


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