Journal Article

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

Sheth, Frenny, Horn, Anselm H.C., Oneda, Beatrice, Latal, Beatrice, Azzarello-Burri, Silvia, Bachmann-Gagescu, Ruxandra, Niedrist, Dunja, Zweier, Markus, Verma, Ishwar C., Boonsawat, Paranchai, Zollino, Marcella, Verloes, Alain, Asadollahi, Reza, Puri, Ratna Dua, Jenni, Oskar, Sticht, Heinrich, Steinfeld, Robert, Lincoln, Sharyn, Passemard, Sandrine, Masood, Rahim, Rodan, Lance, Gogoll, Laura, Drunat, Séverine, Kraemer, Dennis, Rauch, Anita, Steindl, Katharina, Figueiro-Silva, Joana, Joset, Pascal, Papik, Michael, Plecko, Barbara, Datar, Chaitanya

2019

Overview

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. 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). We 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). Our findings enable improved evaluation and genetic counseling of PM and SM patients and further elucidate microcephaly pathways.

• Publisher: Elsevier Inc,Nature Publishing Group US,Elsevier Limited
• Subject: Adolescent / Biomedical and Life Sciences / Biomedicine / Cell Cycle Proteins - genetics / Child / Child, Preschool / DEAD-box RNA Helicases - genetics / Developmental Disabilities - genetics / Developmental Disabilities - pathology / Exome - genetics / Exome Sequencing / Female / Gene Expression Regulation - genetics / Genetic counseling / Genetic Predisposition to Disease / Human Genetics / Humans / Infant / Intellectual Disability - genetics / Intellectual Disability - pathology / Laboratory Medicine / Male / MCPH / Microcephaly / Microcephaly - genetics / Microcephaly - pathology / mitochondria / Mutation / Pedigree / Phenotype / primary microcephaly / secondary microcephaly / Ubiquitin-Protein Ligases - genetics / Wnt Signaling Pathway