Further delineation of the SCAF4-associated neurodevelopmental disorder

Cosima M Schmid^{1

2}, Anne Gregor^{1

2}, Anna Ruiz³, Carmen Manso Bazús³, Isabella Herman^{4

5

6}, Farah Ammouri⁷, Urania Kotzaeridou⁸, Vanda McNiven⁹, Lucie Dupuis¹⁰, Katharina Steindl¹¹, Anaïs Begemann¹¹, Anita Rauch¹¹, Aude-Annick Suter¹¹, Bertrand Isidor¹², Sandra Mercier¹², Mathilde Nizon¹², Benjamin Cogné¹², Wallid Deb¹², Thomas Besnard¹², Tobias B Haack^{13

14}, Ruth J Falb¹³, Amelie J Müller¹³, Tobias Linden¹⁵, Chad R Haldeman-Englert¹⁶, Charlotte W Ockeloen¹⁷, Francesca Mattioli¹⁸, Alexandre Reymond¹⁸, Nazia Ibrahim¹⁹, Shagufta Naz¹⁹, Elodie Lacaze²⁰, Jennifer A Bassetti²¹, Julia Hoefele²², Theresa Brunet²², Korbinian M Riedhammer^{22

23}, Houda Z Elloumi²⁴, Richard Person²⁴, Fanggeng Zou²⁴, Juliette J Kahle²⁴, Kirsten Cremer²⁵, Axel Schmidt²⁵, Marie-Ange Delrue²⁶, Pedro M Almeida²⁷, Fabiana Ramos^{27

28}, Siddharth Srivastava²⁹, Aisling Quinlan²⁹, Stephen Robertson³⁰, Eva Manka³¹, Alma Kuechler³², Stephanie Spranger³³, Malgorzata J M Nowaczyk³⁴, Reem M Elshafie³⁵, Hind Alsharhan^{35

36}, Paul R Hillman³⁷, Leslie A Dunnington³⁷, Hilde M H Braakman³⁸, Shane McKee³⁹, Angelica Moresco⁴⁰, Andrea-Diana Ignat⁴⁰, Ruth Newbury-Ecob⁴¹, Guillaume Banneau⁴², Olivier Patat⁴², Jeffrey Kuerbitz^{6

43}, Susan Rzucidlo⁴⁴, Susan S Sell⁴⁴, Patricia Gordon⁴⁴, Sarah Schuhmann⁴⁵, André Reis^{45

46}, Yosra Halleb⁴⁷, Radka Stoeva⁴⁷, Boris Keren⁴⁸, Zainab Al Masseri⁴⁹, Zeynep Tümer^{50

51}, Sophia Hammer-Hansen⁵², Sofus Krüger Sølyst⁵², Connolly G Steigerwald⁵³, Nicolas J Abreu⁵³, Helene Faust⁵⁴, Amica Müller-Nedebock⁵⁴, Frédéric Tran Mau-Them^{55

56}, Heinrich Sticht⁵⁷, Christiane Zweier^{58

59}

Affiliations

¹ Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland.
² Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland.
³ Center for Genomic Medicine, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain.
⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁵ Department of Neurosciences, Boystown National Research Hospital, Boystown, TX, USA.
⁶ Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁷ The University of Kansas Health System, Westwood, KS, USA.
⁸ Division of Child Neurology and Inherited Metabolic Diseases, Centre for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
⁹ Division of Genetics, Department of Pediatrics, McMaster Children's Hospital, Hamilton, ON, Canada.
¹⁰ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
¹¹ Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
¹² Department of Medical Genetics, CHU Nantes, Nantes, France.
¹³ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
¹⁴ Center for Rare Diseases, University of Tübingen, Tübingen, Germany.
¹⁵ University Children's Hospital, Klinikum Oldenburg, Department of Neuropediatrics, Oldenburg, Germany.
¹⁶ Mission Fullerton Genetics Center, Asheville, NC, USA.
¹⁷ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁸ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
¹⁹ Lahore College for Women University, Lahore, Pakistan.
²⁰ Department of Medical Genetics, Le Havre Hospital, Le Havre, France.
²¹ Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
²² Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.
²³ Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.
²⁴ GeneDx, Gaithersburg, MD, USA.
²⁵ Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
²⁶ Department of Genetics, Université de Montréal, Sainte-Justine University Hospital, Montreal, Canada.
²⁷ Medical Genetics Unit, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal.
²⁸ Centro de Diagnóstico Pré-natal, Unidade Local de Saúde de Coimbra, Coimbra, Portugal.
²⁹ Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
³⁰ Department of Pediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand.
³¹ Center for Rare Disease Essen (Essener Zentrum für Seltene Erkrankungen-EZSE), Universitätsmedizin Essen, Essen, Germany.
³² Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
³³ Praxis für Humangenetik, Klinikum Bremen-Mitte, Bremen, Germany.
³⁴ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
³⁵ Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat, Kuwait.
³⁶ Department of Pediatrics, Health science center, College of Medicine, Kuwait University, P.O. Box 24923, Safat, Kuwait.
³⁷ Department of Pediatrics, Division of Medical Genetics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children's Memorial Hermann Hospital, Houston, TX, USA.
³⁸ Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center & Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands.
³⁹ Belfast HSC Trust, Northern Ireland Regional Genetics Service, Belfast, Northern, Ireland.
⁴⁰ Division of Clinical Genetics, Pediatric Department, Children's Hospital, London Health Sciences Centre, Western University, London, ON, Canada.
⁴¹ Clinical Genetics, University Hospitals Bristol, Southwell St, Bristol, UK.
⁴² Department of Medical Genetics, Toulouse University Hospital, Toulouse, France.
⁴³ Cain Pediatric Neurology Research Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
⁴⁴ Penn State Health Children's Hospital, Department of Pediatrics, Division of Human Genetics, Hershey, PA, USA.
⁴⁵ Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁴⁶ Centre for Rare Diseases Erlangen (ZSEER), Erlangen, Germany.
⁴⁷ Le Mans Hospital, Department of Medical Genetics, Le Mans, France.
⁴⁸ Department of Genetics, Assistance Publique - Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France.
⁴⁹ Department of Pediatrics, Medical Genetics Unit, Qatif Central Hospital, Eastern Health Cluster, Dammam, Saudi Arabia.
⁵⁰ Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁵¹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵² Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁵³ Division of Neurogenetics, Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA.
⁵⁴ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
⁵⁵ Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, CHU Dijon Bourgogne, Dijon, France.
⁵⁶ Génétique des Anomalies Du Développement, INSERM 123, Université de Bourgogne, Dijon, France.
⁵⁷ Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁵⁸ Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland. christiane.zweier@insel.ch.
⁵⁹ Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland. christiane.zweier@insel.ch.

PMID: 39668183
PMCID: PMC12048650
DOI: 10.1038/s41431-024-01760-2

Further delineation of the SCAF4-associated neurodevelopmental disorder

Cosima M Schmid et al. Eur J Hum Genet. 2025 May.

. 2025 May;33(5):588-594.

doi: 10.1038/s41431-024-01760-2. Epub 2024 Dec 12.

Authors

Affiliations

¹ Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland.
² Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland.
³ Center for Genomic Medicine, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain.
⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁵ Department of Neurosciences, Boystown National Research Hospital, Boystown, TX, USA.
⁶ Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁷ The University of Kansas Health System, Westwood, KS, USA.
⁸ Division of Child Neurology and Inherited Metabolic Diseases, Centre for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
⁹ Division of Genetics, Department of Pediatrics, McMaster Children's Hospital, Hamilton, ON, Canada.
¹⁰ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
¹¹ Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
¹² Department of Medical Genetics, CHU Nantes, Nantes, France.
¹³ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
¹⁴ Center for Rare Diseases, University of Tübingen, Tübingen, Germany.
¹⁵ University Children's Hospital, Klinikum Oldenburg, Department of Neuropediatrics, Oldenburg, Germany.
¹⁶ Mission Fullerton Genetics Center, Asheville, NC, USA.
¹⁷ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁸ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
¹⁹ Lahore College for Women University, Lahore, Pakistan.
²⁰ Department of Medical Genetics, Le Havre Hospital, Le Havre, France.
²¹ Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
²² Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.
²³ Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.
²⁴ GeneDx, Gaithersburg, MD, USA.
²⁵ Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
²⁶ Department of Genetics, Université de Montréal, Sainte-Justine University Hospital, Montreal, Canada.
²⁷ Medical Genetics Unit, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal.
²⁸ Centro de Diagnóstico Pré-natal, Unidade Local de Saúde de Coimbra, Coimbra, Portugal.
²⁹ Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
³⁰ Department of Pediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand.
³¹ Center for Rare Disease Essen (Essener Zentrum für Seltene Erkrankungen-EZSE), Universitätsmedizin Essen, Essen, Germany.
³² Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
³³ Praxis für Humangenetik, Klinikum Bremen-Mitte, Bremen, Germany.
³⁴ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
³⁵ Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat, Kuwait.
³⁶ Department of Pediatrics, Health science center, College of Medicine, Kuwait University, P.O. Box 24923, Safat, Kuwait.
³⁷ Department of Pediatrics, Division of Medical Genetics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children's Memorial Hermann Hospital, Houston, TX, USA.
³⁸ Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center & Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands.
³⁹ Belfast HSC Trust, Northern Ireland Regional Genetics Service, Belfast, Northern, Ireland.
⁴⁰ Division of Clinical Genetics, Pediatric Department, Children's Hospital, London Health Sciences Centre, Western University, London, ON, Canada.
⁴¹ Clinical Genetics, University Hospitals Bristol, Southwell St, Bristol, UK.
⁴² Department of Medical Genetics, Toulouse University Hospital, Toulouse, France.
⁴³ Cain Pediatric Neurology Research Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
⁴⁴ Penn State Health Children's Hospital, Department of Pediatrics, Division of Human Genetics, Hershey, PA, USA.
⁴⁵ Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁴⁶ Centre for Rare Diseases Erlangen (ZSEER), Erlangen, Germany.
⁴⁷ Le Mans Hospital, Department of Medical Genetics, Le Mans, France.
⁴⁸ Department of Genetics, Assistance Publique - Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France.
⁴⁹ Department of Pediatrics, Medical Genetics Unit, Qatif Central Hospital, Eastern Health Cluster, Dammam, Saudi Arabia.
⁵⁰ Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁵¹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵² Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁵³ Division of Neurogenetics, Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA.
⁵⁴ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
⁵⁵ Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, CHU Dijon Bourgogne, Dijon, France.
⁵⁶ Génétique des Anomalies Du Développement, INSERM 123, Université de Bourgogne, Dijon, France.
⁵⁷ Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁵⁸ Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland. christiane.zweier@insel.ch.
⁵⁹ Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland. christiane.zweier@insel.ch.

PMID: 39668183
PMCID: PMC12048650
DOI: 10.1038/s41431-024-01760-2

Abstract

While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4 variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant SCAF4-associated neurodevelopmental disorder. The molecular spectrum comprises 25 truncating, eight splice-site and five missense variants. While all other truncating variants were classified as pathogenic/likely pathogenic, significance of one C-terminal truncating variant, one splice-site variant and the missense variants remained unclear. Three missense variants in the CTD-interacting domain of SCAF4 were predicted to destabilize the domain. Twenty-three variants occurred de novo, and variants were inherited in 13 cases. Frequent clinical findings were mild developmental delay with speech impairment, seizures, and skeletal abnormalities such as clubfoot, scoliosis or hip dysplasia. Cognitive abilities ranged from normal IQ to severe intellectual disability (ID), with borderline to mild ID in the majority of individuals. Our study confirms the role of SCAF4 variants in neurodevelopmental disorders and further delineates the associated clinical phenotype.

PubMed Disclaimer

Conflict of interest statement

Competing interests: HZE, RP, FZ and JK are employees of GeneDx, LLC. The remaining authors declare no conflicts of interest. Ethics: The research protocol fulfilled the requirements of the local institutional ethics committee (Kantonale Ethikkommission Bern, 2021-01396). Consent for publication of genetic and clinical data, as well as photographs was obtained from the individuals, their parents, or legal guardians, respectively. The study complied with the principles set out in the Declaration of Helsinki.

Figures

**Fig. 1. *SCAF4* variants in individuals with Fliedner-Zweier syndrome.**
A Exon structure of *SCAF4* (NM_020706.2, NP_065757.1) with newly identified variants and a larger intragenic deletion. Domains color coded according to ensemble, white for non-coding exonic regions, gray for coding exons and color for annotated domains (blue: CTD-interacting domain (CID), purple: Ser/Arg rich domain (SR), red: RNA binding motif (RRM), green: Pro/Gln rich domain (PQ)) [34]. B Conservation of missense variants from *Homo sapiens* to *Drosophila melanogaster*. All variants are fully conserved in tetrapods. Variant positions are highlighted in yellow. Alignment was performed with Clustalw2 [35, 36] with the following reference sequences: *Homo sapiens*: NP_065757.1, *Macaca mulatta*: XP_014988521.2, *Rattus norvegicus*: NP_001032424.2, *Mus musculus*: NP_001404016.1, *Gallus gallus*: NP_001012840.1, *Danio rerio*: NP_001373157.1, *Drosophila melanogaster*: NP_001097394.1. Effect of the p.(Gln118Pro), p.(Leu11Pro) and p.(Ser13Leu) exchanges on the structure of the CTD-interacting domain. C In wt-SCAF4, the amide hydrogen of Q118 forms a hydrogen bond with L114 (green line). D In the Q118P variant, this hydrogen bond cannot be formed because proline lacks an amide proton. Instead, steric clashes occur between the cyclic sidechain of P118 and L114 (magenta arrow), which are expected to decrease helix stability. E L11 of wildtype SCAF4 forms hydrophobic sidechain interactions with V47 and F50 (shown in gray). F In the L11P variant, these hydrophobic interactions cannot be formed by the cyclic sidechain of the proline residue, which is predicted to destabilize the structure of the CTD-interacting domain. Lacking hydrophobic interactions in the variant are highlighted by blue dotted circles. In addition, the cyclic proline sidechain induces steric clashes within the helix (magenta arrow), which further decrease protein stability. G S13 of wildtype SCAF4 forms a sidechain hydrogen bond with K25. Both residues are shown in space-filled presentation and colored according to the atom types; the hydrogen bond between the sidechain oxygen (red) of S13 and the sidechain nitrogen (blue) of K25 is indicated by a green arrow. H In the p.(Ser13Leu) variant, this hydrogen bond cannot be formed by the nonpolar sidechain of L13, which is predicted to destabilize the structure of the CTD-interacting domain. The site of the lacking hydrogen bond is highlighted by a blue dotted circle.

**Fig. 2. Clinical photographs of affected individuals.**
Note the broad nasal bridge in I2, I10, and I45.

See this image and copyright information in PMC

References

1. Proudfoot NJ. Transcriptional termination in mammals: stopping the RNA polymerase II juggernaut. Science 2016;352:aad9926. - PMC - PubMed
1. Elkon R, Ugalde AP, Agami R. Alternative cleavage and polyadenylation: extent, regulation and function. Nat Rev Genet. 2013;14:496–506. - PubMed
1. Becker R, Loll B, Meinhart A. Snapshots of the RNA processing factor SCAF8 bound to different phosphorylated forms of the carboxyl-terminal domain of RNA polymerase II. J Biol Chem. 2008;283:22659–69. - PubMed
1. Haijes HA, Koster MJE, Rehmann H, Li D, Hakonarson H, Cappuccio G, et al. De novo heterozygous POLR2A variants cause a neurodevelopmental syndrome with profound infantile-onset hypotonia. Am J Hum Genet. 2019;105:283–301. - PMC - PubMed
1. Yuryev A, Patturajan M, Litingtung Y, Joshi RV, Gentile C, Gebara M, et al. The C-terminal domain of the largest subunit of RNA polymerase II interacts with a novel set of serine/arginine-rich proteins. Proc Natl Acad Sci USA. 1996;93:6975–80. - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Further delineation of the SCAF4-associated neurodevelopmental disorder

Affiliations

Further delineation of the SCAF4-associated neurodevelopmental disorder

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources