Genomic and phenotypic delineation of congenital microcephaly

Genet Med. 2019 Mar;21(3):545-552. doi: 10.1038/s41436-018-0140-3. Epub 2018 Sep 14.


Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM.

Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis.

Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1.

Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.

Keywords: CNTRL; autozygome; dwarfism; primary microcephaly.

Publication types

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

MeSH terms

  • Adult
  • Child
  • Child, Preschool
  • Dwarfism / genetics
  • Female
  • Genomics / methods
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Microcephaly / genetics*
  • Microcephaly / physiopathology*
  • Mutation / genetics
  • Pedigree
  • Phenotype
  • Whole Exome Sequencing / methods

Supplementary concepts

  • Microcephaly nonsyndromal