Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly

Di Donato, Nataliya; Timms, Andrew E; Aldinger, Kimberly A; Mirzaa, Ghayda M.; Bennett, James T; Collins, Sarah J; Olds, Carissa; Mei, Davide; Chiari, Sara; Carvill, Gemma L.; Myers, Candace T.; Rivière, Jean-Baptiste; Zaki, Maha S; Gleeson, Joseph G; Rump, Andreas; Conti, Valerio; Parrini, Elena; Ross, M. Elizabeth; Ledbetter, David H.; Guerrini, Renzo; Dobyns, William B.

doi:10.1038/gim.2018.8

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Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly

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Author(s): Nataliya Di Donato , MD ¹ , Andrew E. Timms , PhD ² , Kimberly A. Aldinger , PhD ³ , Ghayda M. Mirzaa , MD ³ ^, ⁴ , James T. Bennett , MD, PhD ² ^, ⁴ , Sarah Collins ³ , Carissa Olds ³ , Davide Mei , PhD ⁵ , Sara Chiari , MD ⁵ , Gemma Carvill , PhD ¹² , Candace T. Myers , PhD ⁴ , Jean-Baptiste Rivière , PhD ⁶ , Maha S. Zaki , MD ⁷ , University of Washington Center for Mendelian Genomics, Joseph G. Gleeson , MD, PhD ⁸ , Andreas Rump , PhD ¹ , Valerio Conti , PhD ⁵ , Elena Parrini , PhD ⁵ , M. Elizabeth Ross , MD, PhD ⁹ , David H. Ledbetter , PhD ¹⁰ , Renzo Guerrini , MD ⁵ , William B. Dobyns , MD ³ ^, ⁴ ^, ¹¹

Publication date (Electronic): 19 April 2018

Journal: Genetics in medicine : official journal of the American College of Medical Genetics

Keywords: lissencephaly, subcortical band heterotopia, tubulinopathy, actinopathy, reelinopathy

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Abstract

Purpose

To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia.

Methods

We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes ( ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN and VLDLR) or by whole exome sequencing. 55 patients studied in another institution were added as a validation cohort.

Results

The overall mutation frequency in the entire cohort was 81%. LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%). Other genes accounted for 1% or less of patients. 19% remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia or mild frontal pachygyria.

Conclusions

The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.

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Most cited references 34

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Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.

David Geneviève, Victoire Legrez, Patrick Nitschke … (2013)

The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered γ-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD.

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Somatic mutations in cerebral cortical malformations.

Saumya S Jamuar, Anh-Thu N Lam, Martin Kircher … (2014)

Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated. Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing. Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria. Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).

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The wide spectrum of tubulinopathies: what are the key features for the diagnosis?

Cherif Beldjord, Yoann Saillour, Karine Lascelles … (2014)

Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients' neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized polymicrogyria-like cortical dysplasia (n = 6); and (v) a 'simplified' gyral pattern with area of focal polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype-genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9815831

Journal ID (pubmed-jr-id): 22061

Journal ID (nlm-ta): Genet Med

Journal ID (iso-abbrev): Genet. Med.

Title: Genetics in medicine : official journal of the American College of Medical Genetics

ISSN (Print): 1098-3600

ISSN (Electronic): 1530-0366

Publication date Nihms-submitted: 30 January 2018

Publication date (Electronic): 19 April 2018

Publication date PMC-release: 20 October 2018

Electronic Location Identifier: 10.1038/gim.2018.8

Affiliations

[1 ]Institute for Clinical Genetics, TU Dresden, Dresden, Germany

[2 ]Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, WA, USA

[3 ]Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA. USA

[4 ]Department of Pediatrics, University of Washington, Seattle, WA, USA

[5 ]Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Excellence Centre, A Meyer Children’s Hospital, University of Florence, Florence, Italy

[6 ]Department of Human Genetics, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada

[7 ]Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt

[8 ]Department of Neurosciences, University of California San Diego (UCSD), La Jolla, CA, USA

[9 ]Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY, USA

[10 ]Geisinger Health System, Danville, PA, USA

[11 ]Department of Neurology, University of Washington, Seattle, WA, USA

[12 ]Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Author notes

Corresponding authors: Nataliya Di Donato, MD, Institute for Clinical Genetics, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany, Tel. +49 351 458 5137 Fax. +49 351 458 6337, nataliya.didonato@ 123456uniklinikum-dresden.de ; William B Dobyns, MD, Center for Integrative Brain Research, Seattle Children’s Research Institute, 1900 Ninth Ave, Seattle, WA 98101

Article

Manuscript ID: NIHMS934304

DOI: 10.1038/gim.2018.8

PMC ID: 6195491

PubMed ID: 29671837

SO-VID: 7afcb787-b574-4390-8fdf-86d010aee58e

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Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly

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Abstract

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G3: Genes|Genomes|Genetics

Most cited references 34

Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.

Somatic mutations in cerebral cortical malformations.

The wide spectrum of tubulinopathies: what are the key features for the diagnosis?

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