Faculty Bibliography

Objective: We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy.
Method(s): We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA.
Result(s): Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus.
Significance: This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A, GRIA3, CACNA1C, and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.
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There is a current paucity of information about the obstetric and perinatal outcomes of pregnant novel coronavirus disease 2019 (COVID-19) patients in North America. Data from China suggest that pregnant women with COVID-19 have favorable maternal and neonatal outcomes, with rare cases of critical illness or respiratory compromise. However, we report two cases of pregnant women diagnosed with COVID-19 in the late preterm period admitted to tertiary care hospitals in New York City for respiratory indications. After presenting with mild symptoms, both quickly developed worsening respiratory distress requiring intubation, and both delivered preterm via caesarean delivery. These cases highlight the potential for rapid respiratory decompensation in pregnant COVID-19 patients and the maternal-fetal considerations in managing these cases.

Intra-amniotic infection (IAI) is a common cause of pre-term labour. Manual WBC count on amniotic fluid (AF) has been suggested as a diagnostic test for IAI using a threshold of 50 cells/mm(3). However, no validation studies assessing the accuracy of this method have been performed. AF samples were selected for cell count analysis. WBCs were introduced to 47 AF samples. The results from two technologists' counts were compared with the calculated expected value for WBCs in these samples. Results showed that a comparison between the technologists' WBC count to the expected WBC count yielded R(2) coefficients of 0.62 and 0.78, indicating moderate accuracy. Percentage agreement between the technologists was 67%, indicating low reproducibility. It was concluded that there was moderate correlation between the manual and the expected WBC in the spiked AF samples. Clinicians should be aware of the inaccuracy and imprecision associated with this test when evaluating a patient for IAI.