Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly

Abstract

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.

Keywords: high-throughput nucleotide sequencing; human genetics; medical genetics; molecular genetics; neurology.

Figure 1

Brain imaging of sibling with SUPV3L1 homozygous variant c.1093C>T:p.(Arg365Trp)—the older brother (patient S19a) in panels. (A) Computed tomography (CT) at the early childhood with marked subcortical calcifications in both frontal and parietal lobes (black arrow). (B) Subsequent magnetic resonance imaging (MRI) scans at the middle childhood with marked shrunken bright cerebellum (white arrow). (C–H) Brain MRI at the late adolescence. (E) FLAIR hyperintensities remained in the temporal poles only, (F) atrophic cerebellum but not so FLAIR-hyperintense as earlier and as in the younger sister (white arrow), (G) the corpus callosum is shorter and thinner than normal (black arrow), (D) iron or calcium deposits in the globi pallidi (white arrows), (H) in substantia nigra (white arrows) (C) and in the caudate nuclei (white arrows); brain imaging of sibling with SUPV3L1 homozygous variant c.1093C>T:p.(Arg365Trp)—the younger sister (patient S19b): (I) CT at the early childhood revealed two punctate subcortical calcifications in the right cerebral hemisphere (black arrow). (M) MRI taken as the toddler with normal cerebellum with slight widening of the cerebellar sulci (white arrow). (J–P) MRI at the early adolescence: (J,K) myelination has progressed, but there are white matter hyperintensities on FLAIR sequence in both cerebral hemispheres, (N) shrunken bright cerebellum (white arrow), (O) shortened and thinned corpus callosum (black arrow), (L) iron or calcium deposits in the globi pallidi (white arrows) (P) and in substantia nigra (white arrows).

Figure 2

Venn diagram showing number and symbols of unique and shared genes identified in four studies on different microcephaly patients.