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Somatic Uniparental Disomy of Chromosome 16P in Hemimegalencephaly

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Somatic Uniparental Disomy of Chromosome 16P in Hemimegalencephaly Downloaded from molecularcasestudies.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press COLD SPRING HARBOR Molecular Case Studies | RESEARCH REPORT Somatic uniparental disomy of Chromosome 16p in hemimegalencephaly Nicole G. Griffin,1 Kenneth D. Cronin,2 Nicole M. Walley,3 Christine M. Hulette,4 Gerald A. Grant,5 Mohamad A. Mikati,6,7 Heather G. LaBreche,8 Catherine W. Rehder,8 Andrew S. Allen,9 Peter B. Crino,10 and Erin L. Heinzen1,11 1Institute for Genomic Medicine, Columbia University, New York, New York 10032, USA; 2Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina 27710, USA; 3Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina 27710, USA; 4Department of Pathology, Duke University School of Medicine, Durham, North Carolina 27710, USA; 5Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, USA; 6Division of Pediatric Neurology, Duke University Medical Center, Durham, North Carolina 27710, USA; 7Department of Neurobiology, Duke University, Durham, North Carolina 27708, USA; 8Duke University Health System, Durham, North Carolina 27710, USA; 9Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina 27710, USA; 10Department of Neurology, University of Maryland, School of Medicine, Baltimore, Maryland 21201, USA; 11Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA Abstract Hemimegalencephaly (HME) is a heterogeneous cortical malformation characterized by enlargement of one cerebral hemisphere. Somatic variants in mammalian target of rapamycin (mTOR) regulatory genes have been implicated in some HME cases; however, ∼70% have no identified genetic etiology. Here, we screened two HME patients to identify disease-causing somatic variants. DNA from leukocytes, buccal swabs, and surgically resected brain tissue from two HME patients were screened for somatic variants using genome-wide genotyping arrays or sequencing of the protein- coding regions of the genome. Functional studies were performed to evaluate the molecular consequences of candidate disease-causing variants. Both HME patients evaluated were found to have likely disease-causing variants in DNA extracted from brain Corresponding author: eh2682@ tissue but not in buccal swab or leukocyte DNA, consistent with a somatic mutational cumc.columbia.edu mechanism. In the first case, a previously identified disease-causing somatic single nucleotide in MTOR was identified. In the second case, we detected an © 2017 Griffin et al. This article is overrepresentation of the alleles inherited from the mother on Chromosome 16 in brain distributed under the terms of tissue DNA only, indicative of somatic uniparental disomy (UPD) of the p-arm of the Creative Commons Attribution-NonCommercial Chromosome 16. Using methylation analyses, an imprinted locus on 16p spanning License, which permits reuse and ZNF597 was identified, which results in increased expression of ZNF597 mRNA and redistribution, except for protein in the brain tissue of the second case. Enhanced mTOR signaling was observed commercial purposes, provided in tissue specimens from both patients. We speculate that overexpression of maternally that the original author and expressed ZNF597 led to aberrant hemispheric development in the patient with somatic source are credited. UPD of Chromosome 16p possibly through modulation of mTOR signaling. Ontology terms: hemimegalencephaly; [Supplemental material is available for this article.] pachygyria INTRODUCTION Published by Cold Spring Harbor Laboratory Press There is growing recognition of an important role for de novo variants in specific syndromes doi: 10.1101/mcs.a001735 (Barcia et al. 2012; Heinzen et al. 2012), as well as in more complex phenotypes like autism Cite this article as Griffin et al. 2017 Cold Spring Harb Mol Case Stud 3: a001735 1 of 15 Downloaded from molecularcasestudies.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press COLD SPRING HARBOR Molecular Case Studies Somatic 16p uniparental disomy in hemimegalencephaly (Neale et al. 2012), intellectual disability (de Ligt et al. 2012), and epilepsy (Epi4K Consortium et al. 2013). Because these variants were detected in DNA from leukocytes of patients with a neurological disorder, it is presumed that these variants were newly acquired in parental gametes and present constitutionally in the zygote. However, disease-causing de novo somatic variants may arise postzygotically and be present only in a fraction of the cells in the brain. In fact, somatic variants have previously been reported in conditions associated with medically intractable epilepsy, including hypothalamic hamartoma (Hildebrand et al. 2016), focal cortical dysplasia (Lim et al. 2015; Nakashima et al. 2015), and hemimegalen- cephaly (HME) (HP:0007206), a severe malformation of cortical development characterized by enlargement of one cerebral hemisphere (Lee et al. 2012; Poduri et al. 2012; D’Gama et al. 2015). The mammalian target of rapamycin (mTOR) cascade has been implicated in a number of malformations of cortical development including HME (Crino 2011). Consistent with the known involvement of the mTOR-signaling pathway in HME, all identi- fied somatic variants detected in surgically resected brain tissue occur in genes comprising the phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT)–mTOR pathway and collective- ly are estimated to explain ∼30% of the cases of HME (Lee et al. 2012; Poduri et al. 2012; D’Gama et al. 2015). Previous studies have shown clearly that the mTOR cascade is activated in many cases of HME as evidenced by phosphoactivation of mTOR substrates such as p70S6kinase and ribosomal S6 protein (Ljungberg et al. 2006; Aronica et al. 2007; Boer et al. 2007). Most cases of HME are sporadic, with only one report of familial HME (Leventer et al. 2014), suggesting that new variants likely play an important role in the genetic architecture of this disease. In this study, we sought to identify somatic variants in HME by genetically analyzing paired DNA samples from unaffected cells (leukocytes) and abnormal brain tissue from two patients to identify brain tissue–specific variants. RESULTS Clinical Presentation HME1 is a female of European ancestry. She was developmentally delayed as an infant, and her first seizure (HP:0001250) occurred at 22 mo. Magnetic resonance imaging (MRI) at that time showed generalized overgrowth of the left frontotemporal lobes with regional cortical thickening and shallow sulci consistent with left-sided HME (Fig. 1A). Her seizures became progressively worse between 2 and 3 yr, occurring up to 50 times per day. At 36 mo, HME1 underwent left frontotemporoparietal craniotomy and functional hemispherectomy. Postoperatively, she made developmental gains and was seizure-free for nearly 24 mo. Seizures recurred 24 mo posthemispherectomy. MRI revealed residual fibers crossing the corpus callosum, and electroencephalography (EEG) was supportive of seizures secondarily generalizing from the left hemisphere. The patient then underwent a left-sided anatomic hemispherectomy with completion of the corpus callostomy 26 mo after her first surgery. Postoperatively, the patient has been free of overt seizures for 20 mo. However, EEG still shows brief bursts of spikes in the right hemisphere without clinical correlate. Neuropathologic analysis of a portion of the resected tissue revealed disorganized cerebral cortical cytoarchitecture with balloon cells (Fig. 1B) and persistent radial glial ladders (not shown). She was seen at 8 yr, and the examination showed that she was speaking in short sentences but with relatively severe dysarthria. She could read at the second-grade level. She also presented with right central facial and right upper extremity hemiplegia of the hand and hemiparesis of the arm and leg with the ability to walk and right-sided hyperre- flexia and an upgoing toe on the right. She also had a right homonymous hemianopsia. Griffin et al. 2017 Cold Spring Harb Mol Case Stud 3: a001735 2of15 Downloaded from molecularcasestudies.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press COLD SPRING HARBOR Molecular Case Studies Somatic 16p uniparental disomy in hemimegalencephaly Figure 1. Clinical and neuropathologic findings in HME1 and HME2. (A) T2-weighted magnetic resonance image (MRI) of HME1 showing left-sided hemimegalencephaly (HME). (B) Hematoxylin and eosin (H&E) stain- ing of cortical brain tissue slices showing balloon cells (black arrows) in HME1 (left, 10× and right, 60×). (C) T2- weighted MRI of HME2 showing left-sided HME with pachygyria in the left parietooccipital region. (D) H&E (40×) or NeuN (60×) staining of cortical brain tissue slices from HME2 showing balloon cells (black arrow). HME2 is a female of European ancestry. After an uncomplicated birth, HME2 began hav- ing complex partial seizures at 3 wk and drug-resistant infantile spasms shortly thereafter. MRI showed left HME with a broad area of parietooccipital pachygyria (Fig. 1C). She had a functional hemispherectomy at 6 mo. Postoperatively, subject continued to have seizures, and MRI showed some remaining connection at the corpus callosum and temporal lobe. At 6 mo after the initial surgery, the patient underwent completion of the functional hemispher- ectomy. The patient is currently seizure-free, 36 mo after the second surgery. Neuropatho-
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