Dataset Information

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

ABSTRACT:

Purpose

Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND).

Methods

Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex.

Results

Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners.

Conclusions

A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.

SUBMITTER: Shieh C

PROVIDER: S-EPMC7920571 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

Shieh Christine C Jones Natasha N Vanle Brigitte B Au Margaret M Huang Alden Y AY Silva Ana P G APG Lee Hane H Douine Emilie D ED Otero Maria G MG Choi Andrew A Grand Katheryn K Taff Ingrid P IP Delgado Mauricio R MR Hajianpour M J MJ Seeley Andrea A Rohena Luis L Vernon Hilary H Gripp Karen W KW Vergano Samantha A SA Mahida Sonal S Naidu Sakkubai S Sousa Ana Berta AB Wain Karen E KE Challman Thomas D TD Beek Geoffrey G Basel Donald D Ranells Judith J Smith Rosemarie R Yusupov Roman R Freckmann Mary-Louise ML Ohden Lisa L Davis-Keppen Laura L Chitayat David D Dowling James J JJ Finkel Richard R Dauber Andrew A Spillmann Rebecca R Pena Loren D M LDM Metcalfe Kay K Splitt Miranda M Lachlan Katherine K McKee Shane A SA Hurst Jane J Fitzpatrick David R DR Morton Jenny E V JEV Cox Helen H Venkateswaran Sunita S Young Juan I JI Marsh Eric D ED Nelson Stanley F SF Martinez Julian A JA Graham John M JM Kini Usha U Mackay Joel P JP Pierson Tyler Mark TM

Genetics in medicine : official journal of the American College of Medical Genetics 20200117 5

<h4>Purpose</h4>Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND).<h4>Methods</h4>Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex.<h4>Results</h4>Subjects had clinical ...[more]

PMID: 31949314

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Project description:BackgroundWe aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder.MethodsClinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays.ResultsWe identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype.ConclusionsOur study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

Dataset Information

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

Purpose

Methods

Results

Conclusions

Publications

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

Similar Datasets

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