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Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

ABSTRACT: Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

SUBMITTER: den Hoed J

PROVIDER: S-EPMC7895900 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

den Hoed Joery J de Boer Elke E Voisin Norine N Dingemans Alexander J M AJM Guex Nicolas N Wiel Laurens L Nellaker Christoffer C Amudhavalli Shivarajan M SM Banka Siddharth S Bena Frederique S FS Ben-Zeev Bruria B Bonagura Vincent R VR Bruel Ange-Line AL Brunet Theresa T Brunner Han G HG Chew Hui B HB Chrast Jacqueline J Cimbalistienė Loreta L Coon Hilary H Délot Emmanuèlle C EC Démurger Florence F Denommé-Pichon Anne-Sophie AS Depienne Christel C Donnai Dian D Dyment David A DA Elpeleg Orly O Faivre Laurence L Gilissen Christian C Granger Leslie L Haber Benjamin B Hachiya Yasuo Y Abedi Yasmin Hamzavi YH Hanebeck Jennifer J Hehir-Kwa Jayne Y JY Horist Brooke B Itai Toshiyuki T Jackson Adam A Jewell Rosalyn R Jones Kelly L KL Joss Shelagh S Kashii Hirofumi H Kato Mitsuhiro M Kattentidt-Mouravieva Anja A AA Kok Fernando F Kotzaeridou Urania U Krishnamurthy Vidya V Kučinskas Vaidutis V Kuechler Alma A Lavillaureix Alinoë A Liu Pengfei P Manwaring Linda L Matsumoto Naomichi N Mazel Benoît B McWalter Kirsty K Meiner Vardiella V Mikati Mohamad A MA Miyatake Satoko S Mizuguchi Takeshi T Moey Lip H LH Mohammed Shehla S Mor-Shaked Hagar H Mountford Hayley H Newbury-Ecob Ruth R Odent Sylvie S Orec Laura L Osmond Matthew M Palculict Timothy B TB Parker Michael M Petersen Andrea K AK Pfundt Rolph R Preikšaitienė Eglė E Radtke Kelly K Ranza Emmanuelle E Rosenfeld Jill A JA Santiago-Sim Teresa T Schwager Caitlin C Sinnema Margje M Snijders Blok Lot L Spillmann Rebecca C RC Stegmann Alexander P A APA Thiffault Isabelle I Tran Linh L Vaknin-Dembinsky Adi A Vedovato-Dos-Santos Juliana H JH Schrier Vergano Samantha A SA Vilain Eric E Vitobello Antonio A Wagner Matias M Waheeb Androu A Willing Marcia M Zuccarelli Britton B Kini Usha U Newbury Dianne F DF Kleefstra Tjitske T Reymond Alexandre A Fisher Simon E SE Vissers Lisenka E L M LELM

American journal of human genetics 20210128 2

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different path ...[more]

PMID: 33513338

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Project description:Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype-phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.

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Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Publications

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

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