Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells.

Loss of symmetric cell division of apical neural progenitors drives -related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in and determine that variant type is correlated with disease severity.

Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature.

Ogden syndrome is a rare lethal X-linked recessive disorder caused by a recurrent missense variant (Ser37Pro) in the NAA10 gene, encoding the catalytic subunit of the N-terminal acetyltransferase A complex (NatA). So far eight boys of two different families have been described in the literature, all presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias. Here, we report the ninth case of Ogden syndrome with an independent recurrence of the Ser37Pro variant.

Genetic Analysis in a Swiss Cohort of Bilateral Congenital Cataract.

Importance: Identification of geographic population-based differences in genotype and phenotype heterogeneity are important for targeted and patient-specific diagnosis and treatment, counseling, and screening strategies.

Objective: To report disease-causing variants and their detailed phenotype in patients with bilateral congenital cataract from a single center in Switzerland and thereby draw a genetic map and perform a genotype-phenotype comparison of this cohort.

Design, Setting, And Participants: This clinical and molecular-genetic cohort study took place through the collaboration of the Department of Ophthalmology at the University Hospital Zurich and the Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.

Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.

Purpose: Microcephaly 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.

Methods: We 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).