Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly.

Journal: Genes
Published:
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.

Authors
Mateusz Dawidziuk, Tomasz Gambin, Ewelina Bukowska Olech, Dorota Antczak Marach, Magdalena Badura Stronka, Piotr Buda, Edyta Budzynska, Jennifer Castaneda, Tatiana Chilarska, Elzbieta Czyzyk, Anna Eckersdorf Mastalerz, Jolanta Fijak Moskal, Dorota Gieruszczak Bialek, Ewelina Glodek Brzozowska, Alicja Goszczanska 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, Malgorzata Krajewska Walasek, Katarzyna Kufel, Anna Kutkowska Kaźmierczak, Agata Lipiec, Dorota Maksym Gasiorek, Anna Materna Kiryluk, Hanna Mazurkiewicz, Michał Milewski, Tatsiana Pavina Guglas, Aleksandra Pietrzyk, Renata Posmyk, Antoni Pyrkosz, Mariola Rudzka Dybala, Ryszard Slezak, Marzena Wisniewska, Zofia Zalewska Miszkurka, Elzbieta Szczepanik, Ewa Obersztyn, Monika Bekiesinska Figatowska, Pawel Gawlinski, Wojciech Wiszniewski