The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability

Am J Hum Genet. 2022 Oct 6;109(10):1923-1931. doi: 10.1016/j.ajhg.2022.08.011. Epub 2022 Sep 5.


MTSS2, also known as MTSS1L, binds to plasma membranes and modulates their bending. MTSS2 is highly expressed in the central nervous system (CNS) and appears to be involved in activity-dependent synaptic plasticity. Variants in MTSS2 have not yet been associated with a human phenotype in OMIM. Here we report five individuals with the same heterozygous de novo variant in MTSS2 (GenBank: NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals present with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. In summary, our findings support that mim is important for appropriate neural function, and that the MTSS2 c.2011C>T variant causes a syndromic form of intellectual disability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • DNA, Complementary
  • Drosophila / genetics
  • Humans
  • Intellectual Disability* / genetics
  • Intellectual Disability* / pathology
  • Membrane Proteins
  • Microcephaly* / genetics
  • Microfilament Proteins
  • Mutation, Missense / genetics
  • Nervous System Malformations* / genetics
  • Phenotype


  • DNA, Complementary
  • MTSS2 protein, human
  • Membrane Proteins
  • Microfilament Proteins