Rare variants in dynein heavy chain genes in two individuals with situs inversus and developmental dyslexia: a case report

BMC Med Genet. 2020 May 1;21(1):87. doi: 10.1186/s12881-020-01020-2.

Abstract

Background: Developmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD. However, it is unknown whether there is a common genetic cause to DD and laterality defects or ciliopathies.

Case presentation: Here, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify genetic variants of importance for DD and SI. Individual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): a previously reported variant c.7502G > C; p.(R2501P), and a novel variant c.12043 T > G; p.(Y4015D). Both variants are predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A > G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified.

Conclusions: We identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD and further studies into the association between laterality, ciliopathies and DD are needed.

Keywords: Brain imaging; Developmental dyslexia; L-R asymmetry defects; Primary ciliary dyskinesia; SNVs; Situs inversus; Whole genome sequencing.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Axonemal Dyneins / genetics*
  • Brain / diagnostic imaging
  • Brain / pathology
  • Child
  • Ciliary Motility Disorders / genetics
  • Ciliary Motility Disorders / pathology
  • Dyneins / genetics
  • Dyslexia / diagnostic imaging
  • Dyslexia / genetics*
  • Dyslexia / pathology
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Situs Inversus / diagnostic imaging
  • Situs Inversus / genetics*
  • Situs Inversus / pathology

Substances

  • Axonemal Dyneins
  • DNAH11 protein, human
  • DNAH5 protein, human
  • Dyneins