Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly

Genet Med. 2019 Sep;21(9):2043-2058. doi: 10.1038/s41436-019-0464-7. Epub 2019 Mar 7.

Abstract

Purpose: Microcephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly.

Methods: We performed clinical assessment, high-resolution chromosomal microarray analysis, exome sequencing, and functional studies in 62 patients (58% with primary microcephaly [PM], 27% with secondary microcephaly [SM], and 15% of unknown onset).

Results: We found severity of developmental delay/intellectual disability correlating with severity of microcephaly in PM, but not SM. We detected causative variants in 48.4% of patients and found divergent inheritance and variant pattern for PM (mainly recessive and likely gene-disrupting [LGD]) versus SM (all dominant de novo and evenly LGD or missense). While centrosome-related pathways were solely identified in PM, transcriptional regulation was the most frequently affected pathway in both SM and PM. Unexpectedly, we found causative variants in different mitochondria-related genes accounting for ~5% of patients, which emphasizes their role even in syndromic PM. Additionally, we delineated novel candidate genes involved in centrosome-related pathway (SPAG5, TEDC1), Wnt signaling (VPS26A, ZNRF3), and RNA trafficking (DDX1).

Conclusion: Our findings enable improved evaluation and genetic counseling of PM and SM patients and further elucidate microcephaly pathways.

Keywords: MCPH; genetic counseling; mitochondria; primary microcephaly; secondary microcephaly.

Publication types

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

MeSH terms

  • Adolescent
  • Cell Cycle Proteins / genetics
  • Child
  • Child, Preschool
  • DEAD-box RNA Helicases / genetics
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / pathology
  • Exome / genetics
  • Female
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease*
  • Humans
  • Infant
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Male
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Mutation
  • Pedigree
  • Phenotype
  • Ubiquitin-Protein Ligases / genetics
  • Whole Exome Sequencing
  • Wnt Signaling Pathway

Substances

  • Cell Cycle Proteins
  • SPAG5 protein, human
  • Ubiquitin-Protein Ligases
  • ZNRF3 protein, human
  • DDX1 protein, human
  • DEAD-box RNA Helicases