Novel compound heterozygous variants in the STIL gene identified in a Chinese family with presentation of foetal microcephaly

Eur J Med Genet. 2020 Dec;63(12):104091. doi: 10.1016/j.ejmg.2020.104091. Epub 2020 Oct 24.

Abstract

Primary microcephaly 7 (MCPH7) is an autosomal recessive human neurodevelopmental disorder characterized by microcephaly, sloping forehead, and prominent midface. The STIL gene encodes a protein that regulates the mitotic spindle checkpoint. STIL is the pathogenic gene of MCPH7. Although more than 25 genes have been reported to cause MCPH, many patients lack a molecular diagnosis. The clinical manifestations and genetic factors of MCPH7 remain to be revealed. This research reported two consecutive microcephalic foetuses from unaffected parents. Prenatal ultrasound examination and pre- and postnatal MRI studies were performed. Whole-genome sequencing (WGS) was performed using blood derived from the umbilical cord, and variants were confirmed by Sanger sequencing on the parents. Ultrasound examination showed that the two foetuses suffered primary microcephaly. Using the WGS approach, novel compound heterozygous variants in STIL (c.2344_2347delTTGC, p. Leu782Thrfs*2 in exon 13; c.3838C > T, p. Arg1280Cys in exon 17) were identified in two foetuses with MCPH7. The MRI results of the two siblings were quite similar. Postnatal MRI confirmed the ultrasound and prenatal examinations. The two foetuses had typical microcephaly. Ultrasound and MRI showed that the two foetuses had a thick skull plate, significantly reduced bilateral frontal lobe, upward rotated cerebellum vermis, and dilated fourth ventricle. Our findings have important implications for prenatal diagnosis and genetic counselling for any patients with MCPH7. We extend both the mutational spectrum in the STIL gene and the clinical spectrum of MCPH7.

Keywords: Foetal; Microcephaly; STIL.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Female
  • Fetus / abnormalities*
  • Fetus / diagnostic imaging
  • Heterozygote
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Male
  • Microcephaly / diagnostic imaging
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Mutation
  • Pedigree
  • Phenotype
  • Pregnancy
  • Ultrasonography, Prenatal

Substances

  • Intracellular Signaling Peptides and Proteins
  • STIL protein, human

Supplementary concepts

  • Microcephaly, Primary Autosomal Recessive, 7