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

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 42 individuals carrying SATB1 variants identified overt associated with pathophysiological mechanisms, established by functional assays. Missense the CUT1 and CUT2 DNA-binding domains result stronger chromatin binding, increased transcriptional repression, severe phenotype. In contrast, predicted haploinsufficiency are milder clinical presentation. A similarly mild phenotype is observed for premature protein truncating escape nonsense-mediated decay, which transcriptionally active mislocalized cell. Our results suggest in-depth mutation-specific studies essential full complexity explain phenotypic variability. 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B.B.A. StudyDe Inherited Loss-of-Function Variants TLK2: Genotype-Phenotype Evaluation Distinct Disorder.Am. 2018; 102: 1195-1203Abstract (13) revealed differences between average gestalt when compared deletions 1B–1E S4, S1B).Figure 23D modeling domainsShow caption(A) Schematic representation aligned domains. have high sequence identity (40%) similarity (78%). Note p.Gln402Arg, p.Glu407Gly/p.Glu407Gln, p.Gln525Arg, p.Glu530Gly/p.Glu530Lys/p.Glu530Gln affect equivalent positions within respective domains, while p.Gln420Arg p.Glu547Lys cognate regions.(B) 3D model (left; PDB: 2O4A) (right; based 2CSF) interaction DNA (yellow). Mutated residues highlighted red cyan CUT2, along ribbon visualization corresponding burgundy dark blue, respectively.(C) 3D-homology homeobox (based 1WI3 2D5V) mutated residue shown light gray gray.(B C) detailed descriptions cohort, see Supplemental data.View Large Image ViewerDownload Hi-res image Download (PPT)Table 1Summary characteristics (de novo) variantsAll individualsIndividuals deletionsIndividuals variants%Present/total assessed%Present/total assessedNeurologicIntellectual disability9028/31808/109520/21 Normal103/31202/1051/21 Borderline00/3100/1000/21 Mild268/31606/10102/21 Moderate103/31101/10102/21 Severe196/3100/10296/21 Profound196/3100/10296/21 Unspecified165/31101/10194/21Developmental delay9735/3610012/129623/24Motor delay9234/379211/129223/25Speech delay8932/368310/129222/24Dysarthria306/2091/11565/9Epilepsy6122/36182/118020/25EEG abnormalities7919/24292/710017/17Hypotonia7628/37425/129223/25Spasticity2810/3600/124210/24Ataxia226/27172/12274/15Behavioral disturbances7124/34587/127717/22Sleep disturbances4112/29273/11509/18Abnormal imaging5517/31433/75814/24Regression176/3581/12225/23GrowthAbnormalities pregnancy248/33273/11235/22Abnormalities delivery3210/31556/11204/20Abnormal term delivery62/31101/1051/21 Preterm (<37 weeks)62/31101/1051/21 Postterm (>42 weeks)00/3100/1000/21Abnormal weight birth165/32222/9133/23 Small gestational age (p90)62/32111/941/23Abnormal head circumference birth71/14171/600/8 Microcephaly (p97)71/14171/600/8Abnormal height216/2991/11285/18 Short stature (p97)72/2991/1161/18Abnormal circumference237/31111/9276/22 (p97)00/3100/900/22Abnormal weight4813/27111/96712/18 Underweight (p97)267/2700/9397/18Other featuresFacial dysmorphisms6724/36647/116817/25Dental/oral abnormalities7124/34556/117818/23Drooling/dysphagia3812/32253/12459/20Hearing abnormalities72/30182/1100/19Vision abnormalities5517/31738/11459/20Cardiac abnormalities196/32273/11143/21Skeleton/limb abnormalities3813/34182/114811/23Hypermobility joints308/27303/10295/17Gastrointestinal abnormalities5317/32273/116714/21Urogenital abnormalities175/3000/11265/19Endocrine/metabolic abnormalities309/3000/11479/19Immunological abnormalities328/25252/8356/17Skin/hair/nail abnormalities248/3491/11307/23Neoplasms medical history00/3400/1100/23 Open table tab (A) regions. (B) respectively. (C) gray. (B data. performed assessing consequences cellular localization, activity, overall dimerization capacity. Based 2, supplemental information), selected (observed 14 individuals) interact with, close to, backbone (mosaic c.1220A>G [p.Glu407Gly] c.1259A>G [p.Gln420Arg], c.1588G>A [p.Glu530Lys], c.1588G>C [p.Glu530Gln], c.1639G>A [p.Glu547Lys]), well only (c.2044C>G [p.Leu682Val], novo). As controls, UK10K consortium, healthy normal IQ: c.1097C>T (p.Ser366Leu) (gnomAD allele frequency 6.61e?4), c.1555G>C (p.Val519Leu) (8.67e?6), c.1717G>A (p.Ala573Thr) (1.17e?4) 1A, S3).16Walter Min J.L. Huang Crooks Memari McCarthy Perry J.R. 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Although hint toward additional HPO-based analysis qualitative confirm third entity 0.932; S5 S11, S5). demonstrates analyses5Satterstrom provide first step NDDs, follow-up required gain insight mechanisms understand cohorts Multiple and/or complex increasingly appreciated newly RAC1, POL2RA, KMT2E, PPP2CA.25Haijes H.A. Koster M.J.E. Rehmann Li Hakonarson Cappuccio Hancarova Lehalle Reardon W. Schaefer G.B. al.De Heterozygous POLR2A Cause Syndrome Profound Infantile-Onset Hypotonia.Am. 105: 283-301Abstract 26O’Donnell-Luria A.H. Pais L.S. Faundes V. Wood J.C. Sveden Luria Abou Jamra Accogli Amburgey Anderlid B.M. (DDD) StudyHeterozygous KMT2E Spectrum Epilepsy.Am. 104: 1210-1222Abstract (17) 27Reynhout Jansen Haesen van Belle Munnik S.A. Bongers E.M.H.F. Schieving J.H. Marcelis Amiel Rio Affecting Catalytic C? Subunit PP2A, PPP2CA, Syndromic Intellectual Disability Resembling Other PP2A-Related Disorders.Am. 139-156Abstract 28Reijnders Ansor N.M. Kousi Yue W.W. Tan P.L. Clarkson Clayton-Smith Corning Jones Lam W.W.K. StudyRAC1 Diverse Phenotypes.Am. 466-477Abstract (49) Interestingly, less often explored, mechanistic might underlie well-known (clinically recognizable) NDDs. instance, SATB2, paralog causes Glass syndrome 612313),29Zarate Y.A. Bosanko Caffrey A.R. Bernstein D.M. Williams Berry-Kravis E.M. Mark P.R. Manning M.A. Bhambhani al.Mutation update SATB2 1013-1029PubMed affects localization manner S12 S13).30Lee J.S. Yoo Lim B.C. Kim Choi Chae SATB2-associated presenting Rett-like phenotypes.Clin. 89: 728-732Crossref (23) await discovery well-established syndromes. summary, demonstrate uncharacterized NDDs caused classes locus. combined investigation, models, characterize impacts number uncovering SATB1-associated recommended yet undiscovered fully etiology. K.M., T.B.P., T.S.-S. employees GeneDx, Inc. K.R. employee Ambrygen Genetics. extremely grateful families participating study. addition, wish thank members Genome Technology Center Cell culture facility, Department Genetics, Radboud university center, Nijmegen, processing proband-derived lines. work financially Aspasia grants Dutch Research Council ( 015.014.036 T.K. 015.014.066 L.E.L.M.V.), Netherlands Organization Health Development 91718310 T.K.), Max Planck Society (J.d.H., S.E.F.), Oxford Brookes University , Leverhulme Trust British Academy (D.F.N.), Swiss National Science Foundation 31003A_182632 A.R.), Lithuanian-Swiss cooperation program reduce economic social disparities enlarged European Union (A.R., Ku?inskas) Jérôme Lejeune (A.R.). acknowledge ALSPAC, 100,000 Genomes Project, “TRANSLATE NAMSE,” Genomic Answers Kids (see acknowledgments). collaborations facilitated ERN ITHACA, 24 Reference Networks (ERNs) approved Board Member States, co-funded Commission. aims contribute Solve-RD (E.d.B., H.G.B., S.B., A.-S.D.-P., L.F., C.G., A.J., T.K., A.V., has received funding Union’s Horizon 2020 innovation grant agreement No 779257 . .pdf (16.5 MB) Help pdf files Document S1. S1–S13, S2–S5 S8–S10, acknowledgments, material methods, .xlsx (.05 xlsx details (.02 S6. Summary clinical, findings per S7. List grouped semantic similarity, .zip zip HPOFormat (.JSON file) GenBank, https://www.ncbi.nlm.nih.gov/genbank/OMIM, https://www.omim.org/RCSB Protein Bank, http://www.rcsb.org/pdb/home/home.do