Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

Background: As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate.

Methods: Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES.

Toward a Pathway-Driven Clinical-Molecular Framework for Classifying Autism Spectrum Disorders.

Background: The current classification system of neurodevelopmental disorders is based on clinical criteria; however, this method alone fails to incorporate what is now known about genomic similarities and differences between closely related clinical neurodevelopmental disorders. Here we present an alternative clinical molecular classification system of neurodevelopmental disorders based on shared molecular and cellular pathways, using syndromes with autistic features as examples.

Methods: Using the Online Mendelian Inheritance in Man database, we identified 83 syndromes that had "autism" as a feature of disease, which in combination were associated with 69 autism disease-causing genes.

Functional genomics analysis of Phelan-McDermid syndrome 22q13 region during human neurodevelopment.

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, severely delayed language development and specific facial features, and is caused by a deletion within chromosome 22q13.3. SHANK3, which is located at the terminal end of this region, has been repeatedly implicated in other neurodevelopmental disorders and deletion of this gene specifically is thought to cause much of the neurologic symptoms characteristic of PMS.

MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling.

Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder caused primarily by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a multifunctional epigenetic regulator with known links to a wide spectrum of neuropsychiatric disorders. Although postnatal functions of MeCP2 have been thoroughly investigated, its role in prenatal brain development remains poorly understood. Given the well-established importance of microRNAs (miRNAs) in neurogenesis, we employed isogenic human RTT patient-derived induced pluripotent stem cell (iPSC) and MeCP2 short hairpin RNA knockdown approaches to identify novel MeCP2-regulated miRNAs enriched during early human neuronal development.