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

Boonsawat P, Joset P, Steindl K, Oneda B, Gogoll L, Azzarello-Burri S, Sheth F, Datar C, Verma IC, Puri RD, Zollino M, Bachmann-Gagescu R, Niedrist D, Papik M, Figueiro-Silva J, Masood R, Zweier M, Kraemer D, Lincoln S, Rodan L, Passemard S, Drunat S, Verloes A, Horn A, Sticht H, Steinfeld R, Plecko B, Latal B, Jenni O, Asadollahi R, Rauch A (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Genetics in Medicine Nature Publishing Group: Open Access Hybrid Model Option B

Book Volume: 21

Pages Range: 2043-2058

Journal Issue: 9

DOI: 10.1038/s41436-019-0464-7

Abstract

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

Authors with CRIS profile

Anselm Horn Professur für Bioinformatik Heinrich Sticht Professur für Bioinformatik

Involved external institutions

University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) Sir Ganga Ram Hospital IN India (IN) Universitäts-Kinderspital Zürich CH Switzerland (CH) Boston Children's Hospital US United States (USA) (US) Hôpital Universitaire Robert-Debré FR France (FR) Bharati Hospital And Research Center IN India (IN) Institute of Human Genetics IN India (IN) Fondazione Policlinico Universitario Agostino Gemelli IRCCS IT Italy (IT)

How to cite

APA:

Boonsawat, P., Joset, P., Steindl, K., Oneda, B., Gogoll, L., Azzarello-Burri, S.,... Rauch, A. (2019). Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly. Genetics in Medicine, 21(9), 2043-2058. https://doi.org/10.1038/s41436-019-0464-7

MLA:

Boonsawat, Paranchai, et al. "Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly." Genetics in Medicine 21.9 (2019): 2043-2058.

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