Review

. 2019 Aug;40(8):1013-1029.

doi: 10.1002/humu.23771. Epub 2019 Jun 18.

Mutation update for the SATB2 gene

Yuri A Zarate¹, Katherine A Bosanko¹, Aisling R Caffrey², Jonathan A Bernstein³, Donna M Martin⁴, Marc S Williams⁵, Elizabeth M Berry-Kravis⁶, Paul R Mark⁷, Melanie A Manning⁸, Vikas Bhambhani⁹, Marcelo Vargas⁹, Andrea H Seeley⁵, Juvianee I Estrada-Veras^{10

11

12}, Marieke F van Dooren¹³, Maria Schwab¹⁴, Adeline Vanderver^{15

16}, Daniela Melis¹⁷, Adnan Alsadah¹⁸, Laurie Sadler¹⁹, Hilde Van Esch²⁰, Bert Callewaert²¹, Ann Oostra²², Jane Maclean²³, Maria Lisa Dentici²⁴, Valeria Orlando²⁵, Mark Lipson²⁶, Steven P Sparagana²⁷, Timothy J Maarup²⁸, Suzanne Im Alsters²⁹, Ariel Brautbar³⁰, Eliana Kovitch³¹, Sakkubai Naidu³², Melissa Lees³³, Douglas M Smith³⁴, Lesley Turner³⁵, Víctor Raggio³⁶, Lucía Spangenberg³⁷, Sixto Garcia-Miñaúr³⁸, Elizabeth R Roeder^{39

40}, Rebecca O Littlejohn^{39

40}, Dorothy Grange⁴¹, Jean Pfotenhauer⁴², Marilyn C Jones⁴³, Meena Balasubramanian⁴⁴, Antonio Martinez-Monseny⁴⁵, Lot Snijders Blok^{46

47}, Ralitza Gavrilova⁴⁸, Jennifer L Fish⁴⁹

Affiliations

¹ Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
² Health Outcomes, College of Pharmacy, Department of Pharmacy Practice, University of Rhode Island, Kingston, Rhode Island.
³ Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
⁴ Departments of Pediatrics and Human Genetics, The University of Michigan, Ann Arbor, Michigan.
⁵ Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
⁶ Departments of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center, Chicago, Illinois.
⁷ Division of Medical Genetics, Spectrum Health, Grand Rapids, Michigan.
⁸ Departments of Pathology and Pediatrics, Stanford University School of Medicine, Stanford, California.
⁹ Division of Genetics and Genomic Medicine, Children's Hospital and Clinics of Minnesota, Minneapolis, Minnesota.
¹⁰ Murtha Cancer Center Research Program, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, Maryland.
¹¹ Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
¹² Pediatric subspecialty-Medical Genetics Service, Walter Reed National Military Medical Center, Bethesda, Maryland.
¹³ Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
¹⁴ Genetics Division, Joseph Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, New Jersey.
¹⁵ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
¹⁶ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁷ Department of Translational Medical Science, Section of Pediatrics, Federico II University, Naples, Italy.
¹⁸ Center for Personalized Genetic Healthcare, Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio.
¹⁹ Division of Genetics, Oishei Children's Hospital, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, New York.
²⁰ Department of Human Genetics, University Hospitals Leuven, KU, Leuven, Belgium.
²¹ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
²² Department of Pediatric Neurology, Ghent University Hospital, Ghent, Belgium.
²³ Pediatric Neurology, Palo Alto Medical Foundation, San Jose, California.
²⁴ Medical Genetics, Academic Department of Pediatrics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
²⁵ Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
²⁶ Department of Genetics, Kaiser Permanente, Sacramento, California.
²⁷ Department of Neurology, Texas Scottish Rite Hospital for Children, Dallas, Texas.
²⁸ Department of Genetics, Kaiser Permanente, Los Angeles, California.
²⁹ Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
³⁰ Department of Genetics, Cook Chldren's Medical Center, Fort Worth, Texas.
³¹ PANDA Neurology, Atlanta, Georgia.
³² Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.
³³ Department of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK.
³⁴ Minnesota Epilepsy Group, Saint Paul, Minnesota.
³⁵ Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada.
³⁶ Departamento de Genética, Facultad de Medicina, Montevideo, Uruguay.
³⁷ Unidad de Bioinformática, Institut Pasteur, Montevideo, Uruguay.
³⁸ Department of Medical Genetics, Hospital Universitario La Paz, Madrid, Spain.
³⁹ Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas.
⁴⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
⁴¹ Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medcine, St Louis, Missouri.
⁴² Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
⁴³ Division of Genetics, Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, California.
⁴⁴ Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield, UK.
⁴⁵ Genetics and Molecular Medicine Department, Rare Disease Pediatric Unit, Hospital Sant Joan de Déu, Barcelona, Spain.
⁴⁶ Human Genetics Department, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴⁷ Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
⁴⁸ Departments of Neurology and Clinical Genomics, Mayo Clinic, Rochester, Minnesota.
⁴⁹ Department of Biological Sciences, University of Massachusetts Lowell, Lowell, Massachusetts.

PMID: 31021519
PMCID: PMC11431158
DOI: 10.1002/humu.23771

Review

Mutation update for the SATB2 gene

Yuri A Zarate et al. Hum Mutat. 2019 Aug.

. 2019 Aug;40(8):1013-1029.

doi: 10.1002/humu.23771. Epub 2019 Jun 18.

Authors

Affiliations

¹ Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
² Health Outcomes, College of Pharmacy, Department of Pharmacy Practice, University of Rhode Island, Kingston, Rhode Island.
³ Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
⁴ Departments of Pediatrics and Human Genetics, The University of Michigan, Ann Arbor, Michigan.
⁵ Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
⁶ Departments of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center, Chicago, Illinois.
⁷ Division of Medical Genetics, Spectrum Health, Grand Rapids, Michigan.
⁸ Departments of Pathology and Pediatrics, Stanford University School of Medicine, Stanford, California.
⁹ Division of Genetics and Genomic Medicine, Children's Hospital and Clinics of Minnesota, Minneapolis, Minnesota.
¹⁰ Murtha Cancer Center Research Program, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, Maryland.
¹¹ Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
¹² Pediatric subspecialty-Medical Genetics Service, Walter Reed National Military Medical Center, Bethesda, Maryland.
¹³ Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
¹⁴ Genetics Division, Joseph Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, New Jersey.
¹⁵ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
¹⁶ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁷ Department of Translational Medical Science, Section of Pediatrics, Federico II University, Naples, Italy.
¹⁸ Center for Personalized Genetic Healthcare, Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio.
¹⁹ Division of Genetics, Oishei Children's Hospital, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, New York.
²⁰ Department of Human Genetics, University Hospitals Leuven, KU, Leuven, Belgium.
²¹ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
²² Department of Pediatric Neurology, Ghent University Hospital, Ghent, Belgium.
²³ Pediatric Neurology, Palo Alto Medical Foundation, San Jose, California.
²⁴ Medical Genetics, Academic Department of Pediatrics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
²⁵ Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
²⁶ Department of Genetics, Kaiser Permanente, Sacramento, California.
²⁷ Department of Neurology, Texas Scottish Rite Hospital for Children, Dallas, Texas.
²⁸ Department of Genetics, Kaiser Permanente, Los Angeles, California.
²⁹ Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
³⁰ Department of Genetics, Cook Chldren's Medical Center, Fort Worth, Texas.
³¹ PANDA Neurology, Atlanta, Georgia.
³² Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.
³³ Department of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK.
³⁴ Minnesota Epilepsy Group, Saint Paul, Minnesota.
³⁵ Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada.
³⁶ Departamento de Genética, Facultad de Medicina, Montevideo, Uruguay.
³⁷ Unidad de Bioinformática, Institut Pasteur, Montevideo, Uruguay.
³⁸ Department of Medical Genetics, Hospital Universitario La Paz, Madrid, Spain.
³⁹ Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas.
⁴⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
⁴¹ Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medcine, St Louis, Missouri.
⁴² Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
⁴³ Division of Genetics, Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, California.
⁴⁴ Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield, UK.
⁴⁵ Genetics and Molecular Medicine Department, Rare Disease Pediatric Unit, Hospital Sant Joan de Déu, Barcelona, Spain.
⁴⁶ Human Genetics Department, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴⁷ Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
⁴⁸ Departments of Neurology and Clinical Genomics, Mayo Clinic, Rochester, Minnesota.
⁴⁹ Department of Biological Sciences, University of Massachusetts Lowell, Lowell, Massachusetts.

PMID: 31021519
PMCID: PMC11431158
DOI: 10.1002/humu.23771

Abstract

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

Keywords: SATB2; SATB2-associated syndrome; genotype-phenotype correlation; pathogenic variants; whole exome sequencing.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTERESTS

The authors declare that there is no conflict of interests.

Figures

**FIGURE 1**
Schematic representation of the spectrum of *SATB2* variants previously described and from this study. (a) Splicing and coding exonic pathogenic variants. Splicing variants are represented along the genomic structure of the *SATB2* gene according to NM_015265.3 including 12 exons (boxes) and introns (black horizontal lines). Exonic pathogenic variants are illustrated according to changes at the protein level (p.) by corresponding mutation types as follows: green squares for missense variants, red diamonds for frameshift variants, and yellow circles for nonsense variants. Codons 239 and 283 for nonsense (6 each), and 389 (12 individuals) and 399 (7 individuals) for missense variants are affected by the highest number of pathogenic variants. Diagrams were constructed using Illustrator for Biosequence (IBS1.0.1). (b) *SATB2* intragenic rearrangements. Full boxes correspond to deletions while lighter rectangles to duplications. In case of recurrence of the same exon being involved, the number of occurrences is indicated next to the rearrangement

**FIGURE 2**
(a) Broad halluces from four different individuals. (b) Composite images of individuals with nonsense, missense, and frameshift variants. Across all three images a flat philtrum with thin vermillion of the upper lip can be recognized

See this image and copyright information in PMC

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Mutation update for the SATB2 gene

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Mutation update for the SATB2 gene

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