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GATAD2B-Associated Neurodevelopmental Disorder (GAND): Clinical and Molecular Insights Into a Nurd-Related Disorder

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GATAD2B-Associated Neurodevelopmental Disorder (GAND): Clinical and Molecular Insights Into a Nurd-Related Disorder ARTICLE © American College of Medical Genetics and Genomics GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder Christine Shieh, MD1, Natasha Jones, BS2, Brigitte Vanle, PhD3,4, Margaret Au, MBE, MS5, Alden Y. Huang, PhD6, Ana P. G. Silva, PhD2, Hane Lee, PhD7, Emilie D. Douine, MS8, Maria G. Otero, PhD9, Andrew Choi, BS9, Katheryn Grand, GC10, Ingrid P. Taff, MD11, Mauricio R. Delgado, MD12, M. J. Hajianpour, MD-PhD13, Andrea Seeley, MD14, Luis Rohena, MD15,16, Hilary Vernon, MD-PhD17, Karen W. Gripp, MD18, Samantha A. Vergano, MD19, Sonal Mahida, MGC20, Sakkubai Naidu, MD21,22, Ana Berta Sousa, MD23, Karen E. Wain, MS LGC24, Thomas D. Challman, MD24, Geoffrey Beek, MS, GC25, Donald Basel, MD26, Judith Ranells, MD27, Rosemarie Smith, MD28, Roman Yusupov, MD29, Mary-Louise Freckmann, MD30, Lisa Ohden, GC31, Laura Davis-Keppen, MD32, David Chitayat, MD33,34, James J. Dowling, MD-PhD35, Richard Finkel, MD36, Andrew Dauber, MD37, Rebecca Spillmann, MS CGC38, Loren D. M. Pena, MD-PhD39,40, The Undiagnosed Diseases Network, Kay Metcalfe, MD41, Miranda Splitt, MD42, Katherine Lachlan, MD43,44, Shane A. McKee, MD45, Jane Hurst, MD46, David R. Fitzpatrick, MD47, Jenny E. V. Morton, MBChB FRCP48,49,50, Helen Cox, MD48,49,50, Sunita Venkateswaran, MD51, Juan I. Young, PhD52, Eric D. Marsh, MD-PhD53, Stanley F. Nelson, MD8, Julian A. Martinez, MD-PhD54, John M. GrahamJr, MD, ScD55, Usha Kini, MD56, Joel P. Mackay, PhD2 and Tyler Mark Pierson, MD-PhD 10,57,58 Purpose: Determination of genotypic/phenotypic features of disrupted GATAD2B interactions with its NuRD complex binding GATAD2B-associated neurodevelopmental disorder (GAND). partners. Methods: Fifty GAND subjects were evaluated to determine Conclusions: A consistent GAND phenotype was caused by a range consistent genotypic/phenotypic features. Immunoprecipitation of genetic variants in GATAD2B that include loss-of-function and assays utilizing in vitro transcription–translation products were missense subtypes. Missense variants were present in conserved used to evaluate GATAD2B missense variants’ ability to interact region domains that disrupted assembly of NuRD complex proteins. with binding partners within the nucleosome remodeling and GAND’s clinical phenotype had substantial clinical overlap with other deacetylase (NuRD) complex. disorders associated with the NuRD complex that involve CHD3 and Results: Subjects had clinical findings that included macroce- CHD4, with clinical features of hypotonia, intellectual disability, phaly, hypotonia, intellectual disability, neonatal feeding issues, cardiac defects, childhood apraxia of speech, and macrocephaly. polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novel GATAD2B variants were identified with Genetics in Medicine (2020) 22:878–888; https://doi.org/10.1038/s41436- multiple variant types (nonsense, truncating frameshift, splice-site 019-0747-z variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region Keywords: GATAD2B; NuRD complex; apraxia of speech; domains (CR1 or CR2) of the GATAD2B protein. Immunopre- chromatin remodeling; macrocephaly cipitation assays revealed several of these missense variants INTRODUCTION remodeling activity.1,3 Several neurodevelopmental disorders The nucleosome remodeling and deacetylase (NuRD) complex have been associated with variants in NuRD subunit proteins – is involved in the management of genomic integrity, stem cell that include CHD3, CHD4,andGATAD2B.4 8 Previously differentiation, and neurodevelopment.1,2 This important multi- identified clinical features shared by each of these dominant enzyme complex regulates transcription by linking two disorders include intellectual disability, motor delays, and – independent chromatin-regulating activities: histone deacetylase distinct facies.4 8 De novo CHD4 variants were also associated and adenosine triphosphate (ATP)-dependent nucleosome with hearing loss, bony fusions, palatal abnormalities, Correspondence: Tyler Mark Pierson ([email protected]). Affiliations are listed at the end of the paper. Submitted 23 August 2019; revised 24 December 2019; accepted: 27 December 2019 Published online: 17 January 2020 878 Volume 22 | Number 5 | May 2020 | GENETICS in MEDICINE SHIEH et al ARTICLE 240 kb deletion Exons 1 2 3 4 5 6 7 8 9 10 11 12 K184Nfs2X Q190Afs34X L28Mfs18X Q168X N195Kfs30X Q237X Q274X Gln470X 406 473 1 112 155 199 243 300 510 550 593 GATA Protein CR1 CR2 zinc finger 165 190 340 414 467 480 K52Rfs56X c.1530+1G>A Intron 9 donor E62Dfs45X P257Hfs4X C420S A484Pfs20X D106Gfs5X R174X C420R R478X I266Hfs26X C420R L180P R478X* c.335+2T>G R414Q G278Afs15X R478X* Intron 2 donor Q188X R414Q # P307Hfs12X Q188Efs36X G406R Q477X Q188Efs36X# R116X c.1217-2A>G E476X* Q190Afs34X I316Tfs3X R116X Intron 7 acceptor E476X* Q204X Q325X c.1216+1G>C Q219X c.1419+2T>A L128Cfs24X T328Rfs2X Intron 7 donor Q220X Q349X Intron 8 donor c.465+1G>C Q232X Q399Rfs47X Q359X 1234567890():,; Intron 3 donor c.730-2A>G A383Vfs11X Intron 5 acceptor Deletions Fig. 1 Genomic and protein schematic diagram with GATAD2B-associated neurodevelopmental disorder (GAND) variants. All reported pathogenic GATAD2B variants from our study are represented as deletions, splice-site, or protein changes below the protein diagram. Genomic deletions are represented as bars below the figure. Previously reported variants and deletions are represented with gray letters and bars above the diagram. * monozygotic twins; # somatic mosaic family. hypogonadotrophic hypogonadism, and heart defects (MIM intellectual disability, impaired language development, 617159; CHD4-related syndrome (CHD4RS) or Sifrim–Hitz– strabismus, and characteristic facies. Several additional – Weiss syndrome [SIHIWES]);5 7 while de novo CHD3 variants phenotypic features were identified that included polyhy- were associated with neonatal feeding issues, childhood apraxia dramnios, neonatal feeding difficulties, anisocoria, aortic of speech, joint laxity, undescended testes, and high forehead valve defects, epilepsy, abnormal brain magnetic resonance with frontal bossing (MIM 618205; CHD3-related syndrome images (MRIs), and macrocephaly. This expanded GAND [CHD3RS] or Snijders Blok–Campeau syndrome [SNIBCPS]).4 phenotype closely overlaps other NuRD-associated neuro- Both disorders were also associated with enlarged cerebrospinal developmental disorders indicating that these associated – fluid (CSF) spaces and macrocephaly.4 6 To date, previous proteins (CHD3, CHD4, and GATAD2B) may have conver- reports of GATAD2B-associated neurodevelopmental disorder ging molecular functions and result in clinically related (GAND; MIM 615074) had identified a total of ten subjects who syndromes. possessed deletion or truncating variants in GATAD2B and presented with intellectual disability, impaired language devel- MATERIALS AND METHODS – opment, strabismus, and characteristic facies.8 12 Standard protocol approvals, registrations, and patient In this report, we have characterized the phenotypic data consents of 50 subjects with multiple types of GATAD2B variants with Research protocols and the study were approved by the the purpose of defining the common genetic and clinical Cedars-Sinai Medical Center Institutional Review Board (IRB; features of GAND. Pathogenic variants included deletions protocol Pro00037131). All the participants or their families (3), nonsense (17), truncating frameshift (16), splice-site (7), consented to participation in the study. Informed consent was and missense (7) changes. Missense variants have not been obtained for the publication of all photographs. previously associated with GAND and all of them were Subjects GAND21, GAND24, GAND26, GAND27, located within two highly conserved domains, conserved GAND29, GAND30, and GAND32–35 were identified and region-1 (CR1) and conserved region-2 (CR2) of the referred to our study through the Deciphering Developmental GATAD2B protein (also known as p66β)(Fig.1,TableS1). Disorders (DDD) study (UK Research Ethics Committee Several of these missense variants were shown to disrupt approval: 10/H0305/83, granted by the Cambridge South interactions between the GATAD2B protein and its NuRD REC).13 Authorization for disclosure of recognizable subjects binding partners. All subjects had phenotypes that included in photographs and information was obtained by parents. GENETICS in MEDICINE | Volume 22 | Number 5 | May 2020 879 ARTICLE SHIEH et al Clinical genetic evaluations reported parameters are based on available data with raw data Genomic DNA was extracted from saliva or blood and genetic supplied in parentheses wherever pertinent. testing was performed and analyzed per previous protocols for clinically available trio-based exome sequencing14,15 (N = Plasmids 44; the DDD study; the Undiagnosed Diseases Network; Full-length genes for mouse methyl-binding domain protein- GeneDx, Gaithersburg, MD; Centogene, Rostock, Germany; 3 (MBD3; UniProt ID:Q9Z2D8), and human methyl-binding Baylor College of Medicine, Houston, TX), intellectual domain 2-ɑ (MBD2-ɑ; UniProt ID:Q9UBB5), GATAD2B disability panels (N = 4; GeneDx, Gaithersburg, MD; Uni- (UniProt ID:Q8WXI9), and partial gene sequences for the versity of Chicago, Chicago, IL; Genome Diagnostics Nijme- C-terminal domains (CTD) of chromodomain-helicase gen, Nijmegen, NL), and chromosomal single-nucleotide DNA-binding protein-3 (CHD3; UniProt ID:Q12873), polymorphism (SNP)
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