Genomic and phenotypic delineation of congenital microcephaly

Abstract

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.

Fig. 1. Pie chart showing the grouping and distribution of the variants identified in this cohort into four categories: variants in MCPH genes, variants in genes with established disease phenotypes in humans, variants in genes reported previously as candidate genes, and variants in genes with no established disease phenotypes in humans.

MCPH, microcephaly primary hereditary.

Fig. 2. Graph plot showing the available OFC (upper panel) and height/length (lower panel) data points at birth and on the last clinical evaluation that we collected for the cohort.

Red color: Cases with variants in microcephaly primary hereditary (MCPH) genes. Green: Cases with variants in genes with established disease phenotypes in humans with congenital microcephaly (CM). Orange: Cases with variants in genes reported previously as candidate genes. Blue: Cases with variants in genes with no established disease phenotypes in humans. OFC, occipital frontal circumference.

Fig. 3. Representative magnetic resonance images (MRI) for the cases with pathogenic variant in microcephaly primary hereditary (MCPH) genes and other genes highlighted in this study.

(a) Case 13DG0605 with pathogenic variant in ASPM showing pachygyria. (b) Case 15DG1001 with pathogenic variant in MFSD2A showing hydrocephaly. (c) Case 17DG0679 with a pathogenic variant in STIL showing the partial agenesis of the corpus callosum and pachygyria. (d, e) Case 17DG0680 with a pathogenic variant in CEP152 showing polymicrogyria, severe callosal hypogenesis with inter-hemispheric cyst at left aspect of the falx compressing the left cerebral hemisphere continuous with the third ventricle, and mild dilatation of the lateral ventricles. (f) Case 15DG0077 with a pathogenic variant in BRCA2 showing hypoplastic corpus callosum. (g) Case 13DG0152 with a pathogenic variant in DDX11 showing hypoplastic corpus callosum. (h) Case 12DG1528 with a pathogenic variant in SPDL1 showing virtually no brain in computed tomography (CT) scan. (i) Case with a pathogenic variant in ANKLE2 showing sloping of the forehead along with simplified gyration, partial agenesis of the corpus callosum, and hypoplastic cerebellum.