PurposeMicrocephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly.MethodsWe performed clinical assessment, high-resolution chromosomal microarray analysis, exome sequencing, and functional studies in 62 patients (58% with primary microcephaly [PM], 27% with secondary microcephaly [SM], and 15% of unknown onset).ResultsWe found severity of developmental delay/intellectual disability correlating with severity of microcephaly in PM, but not SM. We detected causative variants in 48.4% of patients and found divergent inheritance and variant pattern for PM (mainly recessive and likely gene-disrupting [LGD]) versus SM (all dominant de novo and evenly LGD or missense). While centrosome-related pathways were solely identified in PM, transcriptional regulation was the most frequently affected pathway in both SM and PM. Unexpectedly, we found causative variants in different mitochondria-related genes accounting for ~5% of patients, which emphasizes their role even in syndromic PM. Additionally, we delineated novel candidate genes involved in centrosome-related pathway (SPAG5, TEDC1), Wnt signaling (VPS26A, ZNRF3), and RNA trafficking (DDX1).ConclusionOur findings enable improved evaluation and genetic counseling of PM and SM patients and further elucidate microcephaly pathways.

High-resolution prenatal microarray testing is a reliable technique that increases diagnostic yield by at least 17.3% when compared with conventional karyotyping, without an increase in the frequency of variants of uncertain significance.

The past decades have seen a remarkable shift in the demographics of childbearing in Western countries. The risk for offspring with chromosomal aneuploidies with advancing maternal age is well known, but most studies failed to demonstrate a paternal age effect. Retrospectively, we analyzed two case data sets containing parental ages from pre-and postnatal cases with trisomies 21, 13 and 18. The reference data set contains the parental ages of the general Swiss population. We dichotomized all couples into two distinct groups. In the first group, the mothers' integral age was as least as the father's age or older. We compared the frequency of cases in nine 5-year intervals of maternal age. In addition, we computed logistic regression models for the binary endpoint aneuploidy yes/no where paternal ages were incorporated as linear or quadratic, as well as smooth functions within a generalized additive model framework. We demonstrated that the proportion of younger fathers is uniformly different between cases and controls of live-born trisomy 21 as well, although not reaching significance, for fetuses over all mother's ages. Logistic regression models with different strategies to incorporate paternal ages confirmed our findings. The negative paternal age effect was also found in pre-and postnatal cases taken together with trisomies 13 and 18. The couples with younger fathers face almost twofold odds for a child with Down syndrome (DS). We estimated odds curves for parental ages. If confirmation of these findings can be achieved, the management of couples at risk needs a major correction of the risk stratification.

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Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel NaV1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that NaV1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)], and compared them to neurons from an epileptic encephalopathy patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower NaV1.2 protein levels. In neurons with the frameshift variant, NaV1.2 mRNA and protein levels were reduced by ~ 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying NaV1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced NaV1.2 levels. By contrast, epilepsy neurons displayed no change in NaV1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency, and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced NaV1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to NaV1.2 dysfunction and can guide further investigations.