Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly
Mateusz Dawidziuk, Tomasz Gambin, Ewelina Bukowska‐Olech, Dorota Antczak‐Marach, Magdalena Badura‐Stronka, Piotr Buda, Edyta Budzyńska, Jennifer Castañeda, Tatiana Chilarska, Elżbieta Czyżyk, Anna Eckersdorf-Mastalerz, Jolanta Fijak-Moskal, Dorota Gieruszczak‐Białek, Ewelina Glodek-Brzozowska, Alicja Goszczańska‐Ciuchta, Malgorzata Grzeszykowska-Podymniak, Barbara Gurda, Anna Jakubiuk‐Tomaszuk, Ewa Jamroz, Magdalena Janeczko, Dominika Jedlińska-Pijanowska, Marta Jurek, Dagmara Karolewska, Adela Kazmierczak, Teresa Kleist, Iwona Kochanowska, Małgorzata Krajewska‐Walasek, Katarzyna Kufel, Anna Kutkowska‐Kaźmierczak, Agata Lipiec, Dorota Maksym-Gąsiorek, Anna Materna‐Kiryluk, Hanna Mazurkiewicz, Michał Milewski, Tatsiana Pavina-Guglas, Aleksandra Pietrzyk, Renata Posmyk, Antoni Pyrkosz, Mariola Rudzka‐Dybała, Ryszard Ślężak, Marzena Wiśniewska, Zofia Zalewska‐Miszkurka, Elżbieta Szczepanik, Ewa Obersztyn, Monika Bekiesińska‐Figatowska, Paweł Gawliński, Wojciech Wiszniewski
Abstract
Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.