Rare metabolic disease mimicking COL4A1/COL4A2 fetal brain phenotype

Abstract

Pathogenic variants of collagen type IV alpha 1 and 2 (COL4A1/COL4A2) genes cause various phenotypic anomalies, including intracerebral hemorrhage and a wide spectrum of developmental anomalies. Only 20% of fetuses referred for COL4A1/COL4A2 molecular screening (fetuses with a suspected intracerebral hemorrhage) carry a pathogenic variant in these genes, raising questions regarding the causative anomaly in the remaining 80% of these fetuses. We examined, following termination of pregnancy or in-utero fetal death, a series of 113 unrelated fetuses referred for COL4A1/COL4A2 molecular screening, in which targeted sequencing was negative. Using exome sequencing data and a gene-based collapsing test, we searched for enrichment of rare qualifying variants in our fetal cohort in comparison to the Genome Aggregation Database (gnomAD) control cohort (n = 71 702). Qualifying variants in pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) were overrepresented in our cohort, reaching genome-wide significance (P = 2.11 × 10^-7 ). Heterozygous PDHA1 loss-of-function variants were identified in three female fetuses. Among these three cases, we observed microcephaly, ventriculomegaly, germinolytic pseudocysts, agenesis/dysgenesis of the corpus callosum and white-matter anomalies that initially suggested cerebral hypoxic-ischemic and hemorrhagic lesions. However, a careful a-posteriori reanalysis of imaging and postmortem data showed that the observed lesions were also consistent with those observed in fetuses carrying PDHA1 pathogenic variants, strongly suggesting that these two phenotypes may overlap. Exome sequencing should therefore be performed in fetuses referred for COL4A1/COL4A2 molecular screening which are screen-negative, with particular attention paid to the PDHA1 gene. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Keywords: COL4A1/COL4A2; PDHA1; corpus callosal dysgenesis; exome sequencing; fetal intracerebral hemorrhage; ventriculomegaly.

Figure 1

Location of pathogenic PDHA1 variants and pedigrees of the three fetuses with qualifying mutations. (a) Protein structure and corresponding domain organization of human PDHA1 protein (protein NP_000275.1). Numbers below the figure represent the first and last coding amino acids for the only protein domain of PDHA1, and the last coding amino acid (AA 390). (b) Pedigrees of the three mutated probands. Males are represented by squares and females by circles, triangles indicate pregnancy not carried to term and diamonds indicate gender not specified. Filled symbols indicate affected individual (confirmed clinically and by magnetic resonance imaging) and empty symbols indicate clinically healthy individual. Diagonal black line indicates deceased individual. WG, gestational weeks; WT, wild type.

Figure 2

Brain imaging in three fetuses carrying pathogenic variants of PDHA1 gene. (a–f) Fetal brain magnetic resonance imaging (MRI) performed at 26 weeks in fetus F1: (a–e) T2-weighted sequences and (f) T1-weighted sequence. (a) Axial image showing heterogeneous content of ventricles and hypointense signal of walls of lateral ventricles, with mild ventricular dilatation and irregular ventricular walls. (b) Coronal image showing severe gyration delay (appearance of agyria), bilateral periventricular pseudocysts (white arrow) and hypersignal of white matter on temporal lobe (black arrow). (c) Sagittal image showing partial agenesis of posterior part of corpus callosum. (d) Parasagittal plane showing highlighted ventricular walls, corresponding to suspected hemorrhage deposits (arrow). (e) Axial plane showing cerebellar hypoplasia. (f) Axial image showing heterogeneous content of ventricles with T1 hypersignals, suggestive of hemorrhagic suffusion (arrow). (g–i) Brain MRI at 30 weeks in fetus F2: axial and sagittal T2-weighted sequences. (g) Parasagittal section showing germinolytic microcysts localized in the ganglionic eminence and organized in ‘string-of-beads’ formation in right lateral ventricular wall (arrow). (h) Axial image showing microcysts present in anterior part of lateral ventricles (arrows) and hypersignal in left temporal white matter. (i) Sagittal section showing thin corpus callosum (arrow). (j–m) Brain MRI at 28 weeks in fetus F3. (j) T2-weighted sagittal sequence showing rudimentary segment of corpus callosum (8 mm, i.e. partial agenesis (arrowhead)) and overall reduction in parenchyma, especially affecting the vermis (hypoplasia (arrow)). (k) T2-weighted coronal sequence of middle part of frontal gyri: frontal horns are unusually enlarged (filled arrowheads) and there is overall reduction in parenchyma with expanded appearance of pericerebral spaces and significant gyration delay of sylvian sulci (*). Corpus callosum is thin (arrow) and there are cystic lesions of periventricular germinolysis under frontal horns and in temporal region (open arrowheads). (l) T2-weighted coronal sequence in anterior part of frontal gyri: frontal horns are enlarged and quadrangular in shape, with irregular walls (arrowheads). There is left frontal paramedian indentation, without schizencephaly (arrow). (m) T2-weighted axial sequence showing overall reduction in parenchyma, wide pericerebral spaces and ventriculomegaly affecting the occipital horns (arrows). Periventricular white matter appears heterogeneous and microcystic (arrowhead) and significant delay in gyration is evident (*). (n) Axial ultrasound image at 28 weeks in fetus F3, showing unusual anterior complex with septal agenesis (filled arrowhead), bilateral ventriculomegaly (arrows), heterogeneous microcystic hyperechoic appearance of periventricular white matter (*) and significant sylvian gyration delay (open arrowhead).

Figure 3

Macroscopic and histological brain features of fetal PDHA1 deficiency. (a–d) Fetus F1, at 27 weeks. (a) Median sagittal slice of right hemisphere showing partial agenesis of the corpus callosum (only third anterior part); arrowheads indicate pericallosal artery. (b) Transverse section of cerebral hemisphere showing left subependymal parietal (arrowhead 1) and temporal (arrowhead 2) pseudocysts (PCs) and temporal thinning (arrowhead 3). (c) Histological image showing subependymal PCs (hematoxylin & eosin staining (HES); original magnification, ×25). (d) Corresponding Perls staining, showing negative result (original magnification, ×25). (e–h) Fetus 2, at 31 weeks. (e) Coronal brain slice showing moderate ventricular dilatation and periventricular PCs (arrowheads). (f) Histological pattern showing multiple frontal PCs (HES; original magnification, ×20). (g) Periventricular subependymal PC (HES; original magnification, ×20). (h) Frontal PCs with negative result for Perls staining (original magnification, ×40). GZ, germinative zone; V, ventricle.