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Genet Med. 2019 Mar 7. doi: 10.1038/s41436-019-0464-7. [Epub ahead of print]

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

Author information

1
Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland.
2
FRIGE's Institute of Human Genetics, FRIGE House, Satellite, Ahmedabad, India.
3
Sahyadri Medical Genetics and Tissue Engineering Facility, Kothrud, Pune and Bharati Hospital and Research Center Dhankawadi, Pune, India.
4
Institute of Medical Genetics & Genomics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India.
5
Unità Operativa Complessa di Genetica Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, and Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Rome, Italy.
6
Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
7
Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
8
Service de Neuropédiatrie, Hôpital Universitaire Robert Debré, APHP, Paris, France.
9
Département de Génétique, Hôpital Universitaire Robert Debré, APHP, Paris, France.
10
Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
11
Division of Pediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
12
Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria.
13
Child Development Center, University Children's Hospital Zurich, Zurich, Switzerland.
14
Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland. anita.rauch@medgen.uzh.ch.
15
Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland. anita.rauch@medgen.uzh.ch.
16
Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland. anita.rauch@medgen.uzh.ch.

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.

KEYWORDS:

MCPH; genetic counseling; mitochondria; primary microcephaly; secondary microcephaly

PMID:
30842647
DOI:
10.1038/s41436-019-0464-7

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